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Requirements, Routes of Administration and Prescription

Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.


World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 111
From Mitochondrial Disturbances to
Energy Requirements
Pierre Singer
Critical Care Medicine, Institute for Nutrition Research, Rabin Medical Center, Beilison Hospital,
Petah Tikva, Israel
Abstract
An organism requires nutrients to produce ATP, but the substrate oxidative process increases oxida-
tive stress. This fine- tuning is centralized in the mitochondria, which is able to react to any excess or
deprivation in nutrients. In normal subjects, these regulations can induce inflammatory effect and
obesity in energy excess and a decrease in oxidative stress in a hypocaloric diet. In the critically ill
patient, the mitochondrial capacity to cope with severe illness not only includes oxygen supply and
nutrient and substrate supply with adequate coupling efficiency of oxidative phosphorylation, but
also limitation of hormonal disturbances, maintenance of mitochondrial gene transcription, and
limitation of the activity of mitochondrial proteases that lead to autophagy. In the macroscopic per-
spective, overfeeding increases glycemia, infection rate, length of ventilation, and length of stay.
Many observational studies correlate hypocaloric regimens with increased complications and mor-
tality. This chapter integrates the mitochondrial mechanisms modeling nutrient administration with
acute illness. Copyright 2013 S. Karger AG, Basel
An organism is very sensitive to variations in the intake of nutrients. Excess substrate
increases oxidative processes, inducing reactive oxygen species and creating messages
to the endothelial reticulum stimulating inflammatory pathways. Nutritional excesses
in the critically ill may increase the oxidative load and alter immune function. In
contrast, hypocaloric regimens may decrease oxidative stress in a comparable way
to metabolic syndrome and so decrease the production of reactive oxidative tissues.
Recently, the debate concerning how many calories to administer to a critically ill
patient has moved from how much to other aspects such as by which route or early
versus late, increasing confusion in the debate [1]. Definitively, mitochondria are at
the center of the problem, being able to react to any deficit or excess in energy and
regulating ATP production. Mitochondrial oxidative phosphorylation is responsible
for over 90% of total oxygen consumption and ATP generation [2]. Four individual
enzyme complexes (I IV) are generated by the mitochondria and can be inhibited by
2 Singer
reactive oxygen and nitrogen species. Therefore, apoptosis and survival may be tightly
linked to bioenergetics status. This has justified an impressive amount of research in
this field and this chapter will attempt to link the function and survival of a critically
ill patient to the ability to use and produce energy.
Energy Generation: The Mitochondria
Mitochondria are cellular organelles characterized by a double membrane structure
common to most cells and organs that maintain intracellular homeostasis through
several key functions. The most important of these is the production of energy that
can be consumed in the cell. Glycolysis is a series of reactions by which glucose is
phosphorylated twice, cleaved and rearranged into two pyruvate molecules. Pyruvate
is converted to lactate by LDH, producing two ATP molecules per pyruvate molecule.
In the presence of oxygen, pyruvate enters the mitochondria from the cytoplasm via
pyruvate dehydrogenase, is converted to acetate, linked to coenzyme A to form acetyl
CoA, and then combined with oxaloacetate to form citrate.
Hans Krebs was the first to describe the process involving enzymes from the mito-
chondrial matrix, namely the tricarboxylic acid or Krebs cycle. This process cre-
ates reducing equivalents stored as NADH- H+, FADH+, or coenzyme Q. Through
the electron transport chain, these electron carriers (fig. 1) transfer energy to form
ATP, passing through four protein complexes, of which complexes I, III, and IV are
involved in pumping of the protons. The energy generated from the gradient is used
by the 5th complex ATP synthetase to convert ADP to high- energy ATP. This process
is only limited by the availability of pyruvate [2].
Table 1 shows the production of energy according to the substrate. If the mito-
chondrial membrane becomes excessively permeable, the proton- motive force will be
disrupted. A large mitochondrial permeability transition pore may be created allow-
ing water and molecules to cross, depleting ATP, promoting mitochondrial swelling,
and initiating apoptosis. Under normal conditions, biogenesis is important and when
it fails, mitochondrial dysfunction occurs. Inversely, survival or critical illness is asso-
ciated with early activation of mitochondrial biogenesis [3].
Brealey et al. [4] described an association between mitochondrial dysfunction,
antioxidant depletion and decreased ATP concentrations that relate to organ failure
and outcome. The mitochondrial capacity to cope with severe illness includes not
only oxygen supply and nutrient and substrate supply with adequate coupling effi-
ciency of oxidative phosphorylation, but also limitation of hormonal disturbances,
maintenance of mitochondrial gene transcription, and limitation of the activity of
mitochondrial proteases that lead to autophagy [3].
In the study by Carre et al. [5], the survivors had an increase in ATP consump-
tion allowed by an early biogenesis response to maintain mitochondrial function.
Variations in ATP in critical illness can influence organ function. Table 2 shows the
From Mitochondrial Disturbances to Energy Requirements 3
requirements of each organ. One of the potential targets is ATP- sensitive potassium
channel, an ion channel critical to the cardiovascular stress response [6]. This chan-
nel can be opened by a fall in intracellular ATP, facilitating nitric oxide activation of
the channel, and decreased ATP production. The ensuing energy failure is the origin
of organ failure development, explaining that not all tissues suffer to the same level
and that survivors have ATP levels preserved in the muscle.
FAD
NADH
NAD
+
FADH
2
Krebs
cycle
O
2
H
2
O
Matrix
Intermembrane
space
Mitochondrial membrane potential
Cyt C Q
I
II
V
IV
III
e
e
e
e
H
+
H
+
H
+
H
+
H
+
H
+
ADP + Pi
ATP
Fig. 1. Substrates metabolized through the Krebs cycle.
Table 1. Production of ATP and the energy equivalents for the main substrates
Glucose Palmitic acid Protein
Molar mass, g 180 256 2,257
Oxygen consumption, l/g 0.747 2.013 1.045
CO
2
production, l/g 0.747 1.4 0.864
RQ 1.00 0.70 0.83
Energy potential, kcal/g 3.87 9.69 4.70
ATP synthesized, kcal/mol 456 1548 450
4 Singer
In enterally fed rats, Briet and Jeejeebhoy [7] demonstrated that hypoenergetic
feeding decreases the activities of complex I III in the mitochondrial fraction of a
soleus muscle as well as the activity of complex I in mononuclear cells. Refeeding by
glucose and mainly protein restores the activities of the mitochondrial complexes.
This precise matching between requirements, the ability of the mitochondria to pro-
duce and the supply of substrates, is at the heart of the debate. Too much or too little
administered energy could be deleterious, and the exact administration of calories is
under investigation and will be discussed below.
Predictive Equations in Critical Illness Are Inaccurate and Therefore Not Helpful
Predictive equations for evaluating caloric needs are inaccurate and unreliable for
patients who are so different from the patient population from whom the equations
were derived [8]. Equations based on weight, height, gender, and age do not reach
accuracy higher than 67%. The more sophisticated equations including minute vol-
ume for ventilated patients, temperature, or diagnosis (trauma, burns) also result in a
large degree of under- or overestimation. Since the intensive care unit (ICU) popula-
tion is heterogeneous, physicians and dieticians should be cautious when prescribing
target energy supply.
Heyland et al. [9] collected data from more than 8,500 patients over 3 years in
hundreds of ICUs around the world and found that not more than 0.8% used indi-
rect calorimetry. More than 30% used an equation based on 25 30 kcal/kg/day. It has
to be noted that any equation based on weight could be inaccurate since observed
weight is misleading in ICU patients. Water administration for fluid resuscitation
could result in overestimating the weight of the patient. About 30% of patients in the
ICU are overweight or obese [10]. Therefore, actual or observed weight is inaccurate.
Ideal weight is recommended, but using such a parameter does not lead to accuracy
greater than 65% in the best case. In obese patients, it is recommended to use ideal
weight and to prescribe 11 14 kcal/kg/day in patients with BMI >30 [11].
Table 2. Contribution of organs to basal oxygen consumption in
relation to weight
% total VO
2
% total weight
Liver 20 2.5
Brain 20 2.0
Heart 10 0.5
Kidneys 10 0.5
Muscles 20 40
Other tissues 20 54.5
From Mitochondrial Disturbances to Energy Requirements 5
Boullata et al. [12] included 395 patients in a study comparing measured energy
expenditure to most of the predictive equations. He found that the most accurate
prediction used the Harris- Benedict equation with a factor of 1.1, but only in 61% of
the patients, while most of the predictions were an underestimation. In patients with
obesity, the Harris- Benedict equation again was the most accurate with a factor of
1.1. The bias was the lowest with Harris- Benedict 1.1 (mean error: 9 kcal/day, range:
+403 to 421 kcal/day), but errors were unacceptable. The authors concluded that
only indirect calorimetry can provide accurate assessment of energy needs.
There appears to be a consensus that indirect calorimetry is the gold standard to
assess resting energy expenditure (REE) in critical care. However, many limitations
impair its more widespread utilization. It is perceived as complicated, despite improved
technologies using automated calibration and hands- on- courses. It requires hemody-
namic and respiratory stability, ventilation using a F
i
o
2
<60%, absence of air leaks,
and no extracorporeal circulation. The measurements may show variations according
to the patient condition, such as physiotherapy, agitation, fever or hypothermia, use
of sedation or curare, and shivering [13]. However, most of a regular ICU population
can be measured accurately on a regular basis. Therefore its use should be extended.
Energy Expenditure in Critical Illness
At a basal state, the body uses oxygen to allow the functioning of membranes and
ion pumps. Precise energy requirements of critically ill patients are unknown.
Underfeeding results in nutritional deficit and immune compromise. Overfeeding
adversely affects glycemic control, ventilator dependency, and body composition, as
well as infection rate [14]. REE can vary from 22 to 34 kcal/kg/day (fig. 2). Kreymann
et al. [15] recently reviewed 75 cohorts including 881 patients with a variety of patho-
logical conditions. Six were performed exclusively in men and three exclusively in
women. These cohorts were compared to healthy volunteers also reported in the lit-
erature form 1950. Mean REE was 28.1 6.5 kcal/kg BW/day (median: 26.9 kcal/kg
BW/day), while the mean REE in healthy volunteers was 23.7 2.0 kcal/kg BW/day
(median 23.6 kcal/kg BW/day), which was significantly lower (p < 0.05). Interestingly,
the distribution in patients with pathological conditions was wider with 65% of them
having a REE >25 kcal/kg BW/day.
The Risks of Underfeeding
According to a study by Kyle et al. [16], the energy and protein needs of hospitalized
patients were not met during the first 5 days of enteral nutrition in ventilated patients
in a Swiss hospital. Only 52% of the energy requirements were met during these 5
days, resulting in an energy deficit of 4,770 kcal. Even after extubation, energy intake
6 Singer
was reduced to about 50% of the requirements for the next week, mainly due to nau-
sea, vomiting, and loss of appetite [17]. For patients remaining chronically ventilated
(requiring mechanical ventilation for >72 h), Higgins et al. [18] showed that they
received a mean of 83% of the energy intake ordered by physicians, but weaning was
not related to nutritional adequacy. Fifty- six percent of these patients were under-
nourished, 30% were overfed, and 14% received feeding within 10% of the required
energy intake. Our group [19] showed that these chronically ill patients were over-
nourished, receiving a mean 1,650 kcal per day, while measured REE was around
1,450 kcal/day. The weaning of these patients was highly influenced by the presence
of a negative water balance.
Multiple observational studies have shown that nutritional support resulting in an
energy deficit is associated with an increase in morbidity and mortality [20 22]. Singh
et al. [23], in another observational study, showed an increase in mortality in ICU
patients having a mean daily calorie delivery of <50% of the recommended value.
Magnuson et al. [24] described clinical conditions that require less energy supply.
Patients after spinal cord injury, stroke, in the progressive stage of ALS, or muscular
dystrophies may have decreased energy expenditure. In fact, since lean body mass is
the main consumer of ATP and oxygen, all the clinical conditions associated with a
decreased lean body mass may also be associated with a decrease in energy expendi-
ture. This is true for ageing and cerebral palsy which should be assessed more pre-
cisely by indirect calorimetry. The use of weight to assess the energy requirements
of obese patients is highly subject to errors; therefore, indirect calorimetry is also
recommended in this condition. Alves et al. [25] looked at 71 measurements in 44
obese patients and found an unacceptable variability when the predictive equations
were matched to the measured REE values.
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REE (kcal/kg BW/day)
Fig. 2. Summary of mean REE measurements in various clinical conditions in recent publications
[14]. Dark gray represents patients in various clinical conditions and light gray represents normal
volunteers. From [15] with permission.
From Mitochondrial Disturbances to Energy Requirements 7
The Risks of Overfeeding
Hyperalimentation is a concept that was created by Dudrick et al. [26] in an arti-
cle written in 1968, introducing the medical world to the science of total parenteral
nutrition. Bistrian et al. [27] in 1974 demonstrated that administration of total paren-
teral nutrition to malnourished surgical patients was life- saving. However, the risks
of overfeeding using parenteral nutrition were recognized very early, and were associ-
ated with increased infectious complications and hyperglycemia [14]. McCowen et al.
[28] underscored the need for aggressive glucose control and Van den Berghe et al.
[29] showed that glucose control with parenteral nutrition improved survival in sur-
gical patients. Recently, Casear et al. [30] (from the same team) studied the effects of
early parenteral nutrition in mainly surgical nonmalnourished patients. The result of
this overfeeding regimen to patients who did not particularly require parenteral nutri-
tion was an increase in infectious complications and length of ventilation. Dissanaike
et al. [31] showed an association between overfeeding and increased blood stream
infections. Grau et al. [32] identified an energy intake cutoff of 25 kcal/kg/day, above
which the risk of developing liver test alterations increased steeply, independently of
the route. In fact, not only the amount but also the distribution of calories between
glucose, fat, and proteins can play a role. Hepatic dysfunction observed in ICU- fed
patients are similar to those observed in type 2 diabetes mellitus and the metabolic
syndrome. They are related to insulin resistance and hyperglycemia, gluconeogenesis,
and de novo fatty acids synthesis. This steatosis can be reversed by a reduction of
carbohydrate and lipids [33].
Tight Calorie Control
From the current literature, it appears that too much administered energy leads to
complications, while hypocaloric regimens lead to undernutrition and complications
such as increased infection, length of ventilation, pressure sores, and more surgical
complications mainly in the malnourished patients. An optimal protein and energy
nutrition targeted according to measured energy expenditure and to 1.2 1.5 g/kg/day
of protein was associated with a 50% decrease in hospital mortality [34]. The authors
identified targets for energy and protein intake, were able to achieve the target, and
showed that mortality can be reduced substantially by optimal nutrition. Prospective
randomized controlled studies to confirm the advantages of matching energy require-
ments to energy delivery have been partially successful. The Tight Calorie Control
Study (TICACOS) [35] was the first to deliver energy according to measurements of
energy expenditure with active dietician intervention, optimized delivery of enteral
nutrition, and complementary parenteral nutrition where required to reach the goal.
This aspect is of importance since the calorie requirement of a critically ill patient
is a moving target. It has been shown that REE varies significantly from day to day
8 Singer
and these findings have been confirmed in our study. Outcomes showed an improve-
ment in hospital mortality, but an increase in length of stay and length of ventila-
tion which may be explained by a trend towards an increase in ventilator- associated
pneumonia. The study group was slightly overfed, reaching a positive energy balance
of +2,000 kcal/14 days due to nonnutritional calories such as those derived from the
sedative agent Diprivan. These results should be confirmed by a large multicenter
study taking into account the extra calories. Another study matching requirements
with nutritional support is the supplemental parenteral nutrition study using paren-
teral nutrition if enteral feeding did not reach 60% of the requirements. Improvement
in morbidity (infection rate, length of stay, length of ventilation) without a change in
mortality was noted and the nonnutritional calories were taken into account, target-
ing delivery closer to requirements [36].
Many other studies [37, 38] have tried to compare different nutritional regimens,
but not according to energy expenditure measurements. The energy administered is
summarized in figure 3 and shows that most of the studies deliver neither energy nor
protein as required. This may be explained by the use of predictive equations or the
inability to achieve the target due to well- known barriers, such as gastric emptying
disturbances, lack of protocols, or reluctance to use parenteral nutrition. Nevertheless,
these studies in fact assessed underfeeding rather than targeted feeding.
0 500 1,000 1,500 2,000 2,500 3,000
Heidegger
Singer
Goal
Casaer
Rice
Arabi
kcal/day
Fig. 3. Mean calorie intake of the study (light gray) and control (dark gray) groups of 5 prospective
randomized studies comparing various energy regimens in ICU patients [30, 35 38]. Goal repre-
sents the extreme low and high ranges of energy expenditure measured by indirect calorimetry
from fig. 2.
From Mitochondrial Disturbances to Energy Requirements 9
1 Singer P, Pichard C: Parenteral nutrition is not the
false route in the ICU. Clin Nutr 2012;31:153 155.
2 Nogueira V, Rigoulet M, Piquet MA, Devin A,
Fontaine E, Leverve X: Mitochondrial respiratory
chain adjustment to cellular energy demand. J Biol
Chem 2001;276:46104 46110.
3 Ruggieri AJ, Levy RJ, Deutschman CS: Mitochondria
dysfunction and resuscitation in sepsis. Crit Care
Clin 2010;26:567 575.
4 Brealey D, Brand M, Heales S, et al: Association
between mitochondrial dysfunction and severity and
outcome of septic shock. Lancet 2002;360:219 223.
5 Carre JE, Orban JC, Re L, et al: Survival in critical
illness is associated with early activation of mito-
chondrial biogenesis. Am J Resp Crit Care Med
2010;182:745 751.
6 Buckely JF, Singer M, Clapp LH: Role of KATP chan-
nels in sepsis. Cardiovasc Res 2006;72:220 230.
7 Briet F, Jeejeebhoy KN: Effect of hypoenergetic feed-
ing and refeeding on muscle and mononuclear cell
activities of mitochondrial complexes I IV in enter-
ally fed rats. Am J Clin Nutr 20001;73:975 983.
8 Walker RN, Heuberger RA: Predictive equations for
energy needs for the critically ill. Resp Care 2009;
54:509 521.
Energy Deficit in Intestinal Failure
Acute inability of the gastrointestinal tract to support nutritional requirements is
common in the ICU. It can range from abdominal distension, gastric emptying dis-
turbances, and vomiting, to ileus and severe diarrhea or prolonged constipation [39].
Several studies have analyzed the wasted calories in the stools of patients suffering
from diarrhea. In a prospective observational study, patients with severe diarrhea
above 350 g feces per day had a loss of 5.6 kcal/g feces calculated by a bomb calorim-
eter [40]. In 13 fully enterally fed and ventilated patients with loose stools, the daily
energy loss in feces was determined using bomb calorimetry [41]. In patients with
malabsorption, defined as an absorption capacity of less than 85%, the total ener-
getic absorption capacity was about 85%. The mean calorie value of energy loss was
300 260 kcal/day. Some patients had a net negative energy balance over 500 kcal/
day. The authors concluded that a daily feces production of 250 g was a good predic-
tor of malabsorption.
Conclusions
As the estimation of energy requirements is challenging in many conditions, e.g.
liver disease, renal failure, or obesity, measuring energy expenditure on an individual
basis by indirect calorimetry is recommended. However, the technique is expensive,
complicated in specific cases, and should be interpreted cautiously. Nevertheless,
this technique most closely approaches that of mitochondrial metabolism. To date,
no randomized controlled trial has answered the question of how many calories we
should administer to our patients [42]. Such trials should be performed in relevant
disease- specific patients at different stages of their disease, since tailored feeding
would appear to be the ideal nutritional support in complex ICU patients.
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Pierre Singer, MD
Critical Care Medicine, Institute for Nutrition Research
Rabin Medical Center, Beilison Hospital
IL 49100 Petah Tikva (Israel)
Tel. +972 3 9376521, E-Mail psinger@clalit.org.il
Requirements, Routes of Administration and Prescription
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 1220
Protein Metabolism and Requirements
Gianni Biolo
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
Abstract
Skeletal muscle adaptation to critical illness includes insulin resistance, accelerated proteolysis, and
increased release of glutamine and the other amino acids. Such amino acid efflux from skeletal mus-
cle provides precursors for protein synthesis and energy fuel to the liver and to the rapidly dividing
cells of the intestinal mucosa and the immune system. From these adaptation mechanisms, severe
muscle wasting, glutamine depletion, and hyperglycemia, with increased patient morbidity and
mortality, may ensue. Protein/amino acid nutrition, through either enteral or parenteral routes, plays
a pivotal role in treatment of metabolic abnormalities in critical illness. In contrast to energy require-
ment, which can be accurately assessed by indirect calorimetry, methods to determine individual
protein/amino acid needs are not currently available. In critical illness, a decreased ability of protein/
amino acid intake to promote body protein synthesis is defined as anabolic resistance. This abnor-
mality leads to increased protein/amino acid requirement and relative inefficiency of nutritional
interventions. In addition to stress mediators, immobility and physical inactivity are key determi-
nants of anabolic resistance. The development of mobility protocols in the intensive care unit should
be encouraged to enhance the efficacy of nutrition. In critical illness, protein/amino acid require-
ment has been defined as the intake level associated with the lowest rate of catabolism. The optimal
protein- sparing effects in patients receiving adequate energy are achieved when protein/amino
acids are administered at rates between 1.3 and 1.5 g/kg/day. Extra glutamine supplementation is
required in conditions of severe systemic inflammatory response. Protein requirement increases dur-
ing hypocaloric feeding and in patients with acute renal failure on continuous renal replacement
therapy. Evidence suggests that receiving adequate protein/amino acid intake may be more impor-
tant than achieving the target energy requirement in order to maintain nitrogen balance and, pos-
sibly, improve patient outcome. Copyright 2013 S. Karger AG, Basel
Protein and Amino Acid Metabolism in Stress Conditions
Critical illness is characterized by loss of body protein, much of which derives from
skeletal muscle (fig. 1) [1]. Amino acid release from this tissue is accelerated to provide
precursors for liver gluconeogenesis and protein synthesis, as well as to support repli-
cation of rapidly turning over cells of the immune system and the intestinal mucosa.
Increased rates of liver protein synthesis include not only the acute phase proteins, but
Protein Metabolism and Requirements 13
also albumin [2]. The plasma albumin pool, however, is often severely depleted due to
an accelerated transcapillary escape rate of this protein. Among all the amino acids, glu-
tamine is released from skeletal muscle at the highest rate [3]. Glutamine is a major fuel
for rapidly dividing cells and for the immune system; it is also a precursor for gluco-
neogenesis, nucleic acid synthesis, and ammonia formation in the kidney. Glutamine is
stored as free amino acid in the skeletal muscle cytoplasm and rapidly released through
transmembrane outward transport systems in stress conditions. Its intramuscular con-
centration is much higher than that of the other amino acids (i.e. 10 vs. 0.1 0.5 mm/l), and
rapidly decreases in critical illness leading to depletion of this amino acid [3]. In stressed
conditions, muscle glutamine de novo synthesis is not accelerated enough to match the
increased rate of peripheral utilization [4]. In critical illness, muscle glutamine depletion
is proportional to disease severity and is associated with poor outcome [5]. Enteral and
parenteral glutamine supplementation has been shown to decrease the rate of infections
and decrease mortality in patients with severe trauma, burns, and sepsis [6, 7].
Muscle catabolism initiates in the early phase of sepsis or severe trauma, and con-
tinues to be activated at later stages until metabolic abnormalities begin to recover
[1]. Muscle loss and weakness in severely ill patients are known to increase morbidity
and mortality. Activation of the ubiquitin- proteasome proteolytic pathway represents
the key factor leading to muscle wasting [8]. Protein synthesis can be either impaired
or accelerated depending on the balance between inhibiting factors and an increased
intracellular amino acid availability derived from accelerated proteolysis [9]. Sepsis
and severe trauma are characterized by rapid increases of plasma levels of inflamma-
tory mediators and stress hormones [10]. Circulating mediators, especially proinflam-
matory cytokines and cortisol, directly activate protein degradation and inhibit protein
Skeletal muscle
F Glutamine efux
F Proteolysis
insulin resistance
Liver
F Gluconeogenesis
F Acute phase protein
F Urea synthesis
F Albumin synthesis
Increased urinary
nitrogen excretion
Amino acids
f Glutamine
F Glucose
F Urea
f Albumin
Increased albumin
transcapillary escape
Immune system
F Cell turnover
F Glutamine uptake
F Glucose uptake
Immunosuppression
Bloodstream
Endothelial dysfunction
Fig. 1. Mechanisms of muscle wasting, glutamine depletion, hyperglycemia, and hypoalbuminemia
in critical illness.
14 Biolo
synthesis through endocrine mechanisms. Critical illness is also characterized by
severe impairment of insulin- mediated glucose uptake in skeletal muscle and acceler-
ated glucose output from the liver leading to hyperglycemia. Poor glucose control and
insufficient insulin administration may also contribute to downregulation of muscle
protein synthesis [11]. In addition to the catabolic effects of hyperglycemia and circu-
lating mediators, several factors intrinsic to skeletal muscle can contribute to protein
loss. Muscle gene expression is directly modulated in sepsis leading to up- or downreg-
ulation of intrinsic mediators, as cytokines and insulin like growth factor- 1, which are
capable of regulating protein kinetics with autocrine mechanisms. Sepsis is associated
with redox unbalance, as shown by increased myofibrillar protein carbonylation. This
abnormality can directly activate the ubiquitin- proteasome pathway. Muscle unload-
ing is also a major intrinsic determinant of muscle wasting in critical illness.
Immobility and Physical Inactivity
While physical activity is necessary to maintain skeletal muscle mass, inactivity is asso-
ciated with loss of muscle mass and impaired function. In critically ill patients, muscle
unloading, due to bed rest, neurological impairment, or pharmacological sedation, sig-
nificantly contributes to skeletal muscle wasting. Type I slow oxidative fibers are partic-
ularly affected during muscle unloading. The catabolic response mediated by unloading
is associated with redox unbalance in skeletal muscle [12]. In order to understand the
mechanisms of inactivity- mediated muscle wasting, the anabolic efficiency of amino
acid intake to stimulate protein synthesis has been determined during experimental
bed rest in healthy volunteers using stable isotope techniques [13]. Results indicated
that during bed rest, amino acid- mediated stimulation of whole body protein synthesis
was impaired by about 15 20% as compared to the ambulatory condition. Mechanisms
included impaired activation of the mTOR pathway and decreased microcirculation and
nutritive blood flow in skeletal muscle associated with decreased muscle contraction.
The combination of two or more catabolic factors with inactivity may act syner-
gistically to accelerate muscle wasting. In healthy volunteers, caloric restriction, at the
level of 80% of the requirement, tripled lean body mass loss after 2 weeks of experi-
mental bed rest [14]. In addition, the muscle catabolic effects of a low- dose cortisol
infusion were four times greater during bed rest than in the ambulatory condition
[15]. Therefore, we predict that the combination of systemic inflammation, increased
stress hormone secretion, inactivity, and low energy intake may greatly accelerate
protein wasting of patients.
In contrast to inactivity, physical exercise ameliorates the efficiency in using
dietary protein [16]. In healthy subjects, the anabolic efficiency of an amino acid load
is doubled when given before or after a resistance exercise session. Recent evidence
demonstrates that early mobilization and progressive exercise have significant ben-
efits for intensive care patients. These results should encourage the development of
Protein Metabolism and Requirements 15
mobility protocols in the intensive care unit [17]. Future studies should determine the
optimal type and dosing of exercise in relation to protein nutrition.
Anabolic Resistance
The concept of decreased anabolic efficiency of protein nutrition in disease states was first
described in 1930 by Sir David Cuthbertson, who showed that in a patient with severe
trauma, receiving about 1.5 g/kg/day of dietary protein, the rate of urinary nitrogen excre-
tion was about twice greater than the rate of nitrogen intake. This evidence suggested
that anabolic efficiency of such a generous amount of dietary protein was dramatically
reduced, thereby explaining the rapid loss of body protein observed in this patient, espe-
cially at the level of skeletal muscle [18]. In addition to critical illness and physical inactiv-
ity, anabolic resistance to protein/amino acid intake has been demonstrated in aging and
in a number of chronic diseases, such as liver cirrhosis, chronic obstructive pulmonary
disease, kidney and heart failure, cancer, etc. Mechanisms leading to anabolic resistance
include cytokine and stress hormone secretion, immobility and physical inactivity, low
energy intake and availability, vasoconstriction, and decreased nutritive blood flow. The
physiological protein requirement is traditionally defined as the lowest protein intake
sufficient to achieve neutral body protein balance. In healthy individuals, the lowest pro-
tein requirement to achieve neutral nitrogen balance is about 0.8 g/kg/day. In conditions
of anabolic resistance, protein intake should be increased and neutral protein balance
may be achieved by increasing protein intake to levels higher than 0.8 g/kg/day. However,
many disease states including cancer, critical illness, and immobility are characterized by
unavoidable wasting of body protein despite optimal nutrition.
Requirements
In critical illness, protein/amino acid requirement has been defined as the intake level
associated with the lowest rate of catabolism. Body protein balance is not further
improved by increasing protein intake above this level. The anticatabolic effects of dif-
ferent rates of protein delivery or amino acid infusion have been assessed in hetero-
geneous groups of critically ill patients receiving artificial nutrition, either enteral or
parenteral. In many studies, the effects of different levels of protein/amino acid intakes
on nitrogen balance were influenced by variations in energy balance. It is well estab-
lished that a low- energy intake worsens protein wasting in critical illness [19]. In bed-
resting volunteers, either undernutrition or overfeeding accelerated lean body mass
wasting at a fixed level of protein intake [14, 20]. The optimal protein- sparing effects
in critically ill patients receiving adequate energy were achieved when protein/amino
acids were administered at rates between 1.3 and 1.5 g/kg/day [21 24]. No further
advantages were observed when more protein/amino acids were provided to these
16 Biolo
patients. Evidence suggests that receiving adequate protein/amino acid intake may
be more important than achieving the target energy requirement (as determined by
indirect calorimetry) to maintain nitrogen balance [25, 26]. In agreement with these
observations, the ESPEN guidelines suggest that critically ill patients should receive
about 1.31.5 g/kg ideal body weight/day of a balanced amino acid mixture in con-
junction with an adequate energy supply [7]. When parenteral nutrition is indicated
in critically ill patients, the amino acid solution should contain 0.20.4 g/kg/day of
l- glutamine (e.g. 0.30.6 g/kg/day alanyl- glutamine dipeptide). These recommenda-
tions may not apply to all patients. In acutely ill patients receiving hypocaloric feeding,
nitrogen requirements may be increased by about 2530% [7].
Acute renal failure is a highly catabolic state due to uremic toxicity, enhanced
inflammatory response, metabolic acidosis, insulin resistance, catabolic hormone
secretion, and activation of protein catabolism by artificial dialysis membranes. In
patients with acute renal failure, starvation further augments the catabolic response
and malnutrition has been identified as a major determinant of morbidity and mor-
tality. Evidence suggests a higher protein/amino acid requirement in critical illness
with acute renal failure [27, 28]; however, the optimal amount of protein/amino acid
intake for this condition is unknown.
The ESPEN guidelines suggest that critically ill patients on continuous renal replace-
ment therapy should receive about 1.5 g/kg/day of protein/amino acid. As the process
of dialysis can remove 1015% of plasma amino acid turnover, a further increase in
protein/amino acid intake of 0.2 g/kg/day is required to account for such amino acid
losses [29]. In critically ill patients with acute renal failure on conservative therapy, a
high protein/amino acid intake accelerates urea production and can increase nitrogen
load to the kidney. On the other hand, a low protein/amino acid intake can increase
lean body mass wasting and affect patient outcome, while an increased intake may
increase renal perfusion and glomerular filtration rate. The optimal amount of pro-
tein/amino acid intake in these patients has not been clearly defined. Current guide-
lines suggest a protein/amino acid intake up to 1 g/kg/day [29]. Nonetheless, evidence
suggests that an increased protein/amino acid intake in nonoliguric acute renal failure
patients may improve nitrogen balance without aggravating renal function [30].
The ESPEN guidelines for parenteral nutrition in the intensive care unit recom-
mend normalizing protein/amino acid requirements per kg ideal body weight in order
to avoid overfeeding in obese or edematous patients. In many studies, protein intake
has been normalized per kg actual body weight, while lean body mass is the true deter-
minant of protein requirement. Thus, the use of either ideal or actual body weight
leads to underfeeding in some patients and overfeeding in others. It has been recently
proposed to normalize the protein target per actual body weight only in the case of
BMI between 20 and 30. In the case of BMI greater than 30, protein target (g/kg/day)
should be multiplied by 27.5 and by the square of height (m). In the case of BMI lower
than 20, the protein target (g/kg/day) should be multiplied by 20 and by the square of
height (m) [31]. The same authors recommend using preadmission body weight [31].
Protein Metabolism and Requirements 17
The Concept of Protein- to- Energy Ratio
Evidence indicates that energy balance can affect protein requirement. It is well known
that in energy- restricted obese patients, protein requirement should be increased
in order to maintain nitrogen balance. In physiological conditions, physical exer-
cise and inactivity inversely regulate energy and protein requirements. Immobility
and physical inactivity lead to decreased energy needs, while protein requirements
are increased because of development of anabolic resistance [13]. Malnourished
physically inactive patients are characterized by low energy requirement while their
protein requirement is relatively increased. Critical illness is characterized by simul-
taneous increases in resting metabolic rate and nitrogen loss. These two parameters,
however, are poorly correlated, as the interindividual variability is much greater
for nitrogen loss than for energy expenditure [32]. These data, therefore, provide
evidence against the concept of a fixed protein- to- energy ratio in all conditions.
Increased provision of protein/amino acids relative to energy intake is required in
patients with impaired muscle activity, poor nutritional status, and severe wasting of
body protein.
Minimum versus Optimal Requirements
In contrast to energy requirement, which can be accurately assessed by indirect
calorimetry, methods to determine individual protein/amino acid requirement
are not currently available. In critically ill patients, the minimum protein/amino
acid requirement is defined as the intake level associated with the lowest rate of
catabolism (fig. 2). Body protein balance cannot be further improved by increasing
protein intake above this level. The rate of catabolism is traditionally determined
at the whole body level using the nitrogen balance technique or the turnover rate
of essential amino acids as determined by stable isotopes and mass spectrometry.
These techniques provide information on average turnover and balance, pooling
together all individual body proteins. However, a greater amino acid availability
could be required in stress conditions to promote synthesis of specific proteins,
such as those related to cell turnover or immune response, or to replace highly
turning- over amino acids, such as glutamine or arginine, that are depleted in stress
conditions. In addition, specific amino acids are associated with nonanabolic
actions, as promotion of insulin sensitivity, modulation of the immune function,
maintenance of the redox status, etc. Thus, the optimal intake could be greater than
the minimum amount of protein/amino acid required to achieve the lowest whole
body protein catabolism.
Markers for defining an optimal protein intake in critical illness are difficult
to identify. These may include intracellular levels of specific amino acids, rates of
turnover of specific proteins or specific physiological functions (muscle strength,
18 Biolo
immune function, insulin sensitivity, redox balance, nitric oxide availability, etc.).
Clinical markers, however, should include patient survival, complications, length of
hospital stay, etc. Few studies have assessed the effects of adequate nutrition on clini-
cal outcome of intensive care patients. In all studies, fixed protein- to- energy ratios
have been applied to both the intervention and control groups [33, 34]. The results
of these studies indicate that not only underfeeding, but also overfeeding, may be
associated with poor patient outcome, suggesting a narrow therapeutic window of
energy provision in intensive care patients. Observational studies have shown that
an adequate intake of protein and amino acids may be associated with lower mortal-
ity [35 37], suggesting that the hypothesis that an optimized provision of protein/
amino acids relative to energy would improve outcome of patients should be directly
tested in randomized trials.
Protein
amino acid
intake
Protein
degradation
Protein synthesis
- Contractlle protelns (skeletal muscle, heart)
- Acute phase protelns
- |mmune system protelns
- Albumln
- Structural and membrane cell protelns
- Lnzymes
- Hormones
- etc.
Oxidation
Urea
Free
amino acid
pool
De novo synthesis
(glutamlne,
alanlne, etc.)
Pegulatlon of speclc metabollc pathways
- Glutamlne r fuel for lmmune cells and
enterocytes, gluconeogenesls, nuclelc
acld synthesls, lnsulln sensltlvlty
- Arglnlne r nitric oxide synthesis
- Cystelne r glutathlone synthesls
- Alanlne r gluconeogenesls
- Leuclne r muscle proteln synthesls,
lnsulln sensltlvlty
- Threonlne r wound heallng
- etc.
Fig. 2. Minimum vs. optimal protein/amino acid requirement. Free amino acids may derive from
proteolysis, dietary intake, or de novo synthesis, and they may be utilized for protein synthesis, urea
formation, or regulation of several metabolic pathways. Minimum protein/amino acid requirement
is defined as the intake level associated with the lowest rate of nitrogen loss through oxidation and
urea formation. However, greater amino acid availability could be required in stress conditions to
promote synthesis of specific proteins or to promote specific metabolic pathways. Thus, the optimal
intake could be greater than the minimum amount of protein/amino acid required to achieve the
lowest whole body protein catabolism.
Protein Metabolism and Requirements 19
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Gianni Biolo, MD, PhD
Clinica Medica, Ospedale di Cattinara
Strada di Fiume 447
IT 34149 Trieste (Italy)
Tel. +39 040 399 4532, E- Mail biolo@units.it
Requirements, Routes of Administration and Prescription
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 2131
How to Choose the Route
Irina Grecu
Anaesthetics Department, University College Hospital, London, UK
Abstract
Choosing the route for nutrition support delivery is one of the main steps in the algorithm of provid-
ing successful nutrition to the critically ill, but it is certainly not an easy process. The rationale should
be guided not only by principles like physiology and benefit versus harm, but also by individual
patient factors like feasibility, contraindications, predicted versus actual tolerance, and (most impor-
tant) the timing for starting food delivery. Although oral nutrition is the more physiological route for
feeding, it is seldom possible or sufficient in critically ill patients. Enteral nutrition, in the form of tube
feeding, remains the best option in the absence of absolute contraindications, but many other factors
should be taken into account. These include the importance of starting early and trying to achieve
target nutrients delivery early, especially in previously undernourished or in most severely ill patients,
as well as the gastrointestinal intolerance present in the majority of critically ill patients. Parenteral
nutrition is an alternative route for nutrition delivery when the enteral one is impossible or insuffi-
cient. The most common complication when choosing this route is overfeeding, which has been asso-
ciated with increased complications rate. On the other hand, the most common complication of
enteral nutrition is underfeeding, which has also been associated with worse outcome and even
increased mortality. Combining enteral with supplemental parenteral nutrition is therefore a rational
approach for providing early and adequate nutritional support in the most severely ill patients.
Copyright 2013 S. Karger AG, Basel
The best route for food delivery in critically ill patients has been and still is one of
the most controversial issues in critical care. Throughout the last decades, many ran-
domized controlled trials (RCTs) looked at advantages and disadvantages of possible
routes, in terms of clinical benefit, potential harm, and costs. Although in the 1980s,
parenteral had been the preferred route for feeding in intensive care, it has progres-
sively been replaced by the enteral access in the early 1990s [1], mainly because of
lower complication rates and costs associated with the latter [2]. At present, there is a
clear trend towards promoting safer and more efficient parenteral nutrition in criti-
cally ill patients, either alone or in combination with the enteral route [3].
Choosing the route for nutrition support delivery is one of the main steps in the algo-
rithm of providing successful nutrition to the critically ill, but certainly it is not an easy
22 Grecu
process. The rationale should be guided by principles like physiology and benefit versus
harm, as well as individual patient factors like feasibility, contraindications, predicted
versus actual tolerance, and most important, the timing for starting food delivery.
From a physiological point of view, oral nutrition is obviously the optimal route,
but this is seldom possible in truly critically ill patients as the vast majority of them
are sedated and ventilated, or may have other forms of organ support. Moreover,
they receive many different medications, most of which are strong analgesics which
may induce nausea. Last but not least, we must remember one of the most common
symptoms of any serious disease is anorexia. Therefore, not only is oral nutrition not
possible in the majority of critically ill patients, but even when it is possible, it is
insufficient most of the time. The use of oral feeding in the intensive care unit (ICU)
is often reserved for short stayers and for patients in the recovery phase, when oral
supplements are introduced progressively, alongside tube feeding or parenteral nutri-
tion, while the latter are gradually withdrawn.
Following the similar most physiological route rationale, the next access to choose
would be tube feeding. Although both oral (in the form of sip feeding or oral supple-
ments) and tube feeding are routes for delivering enteral nutrition, it is common in the
literature and daily practice to use the term enteral nutrition for tube feeding only [4].
As oral nutrition in ICU patients is discussed elsewhere in this textbook, this chapter
will focus on enteral nutrition in the form of tube feeding. The vast majority of ICU
patients can and should be fed into the stomach [4]. For the few situations when intra-
gastric nutrition is not tolerated (i.e. after upper gastrointestinal tract surgery, or in
case of refractory gastroparesis), postpyloric feeding (preferably jejunal) is indicated.
A world of literature exists comparing enteral and parenteral nutrition, and even
today, controversies and debate still exist. Ongoing multicenter trials are now inves-
tigating the risk/benefit ratio of enteral and parenteral nutrition in patients with a
functional gastrointestinal tract [5].
Although it is hard to deny that enteral nutrition should be the first option in
the absence of absolute contraindications, many other factors should be taken into
account. These include the importance of starting early and trying to achieve tar-
get nutrients delivery early, especially in previously undernourished or in the most
severely ill patients, as well as the gastrointestinal intolerance present in the majority
of critically ill patients.
Enteral versus Parenteral Nutrition
This is probably the most famous controversy in critical care nutrition and the fact that
large, multicenter trials are still investigating it [5] proves it is far from being solved.
Two meta- analyses and a systematic review published in 2004 and 2005 included
trials published between 1980 and 2002 and compared enteral with parenteral
nutrition [2, 6, 7]. The authors found increased (infectious) complications with the
How to Choose the Route 23
parenteral route, while no difference in mortality and even decreased mortality with
early parenteral compared to late enteral feeding was shown [7].
The main reason for increased infectious morbidity is probably overfeeding, which
was common to parenteral nutrition practice in the past, but partly also the composi-
tion of old parenteral solutions (i.e. the lipid profile).
Most importantly, the comparison is automatically biased by the fact that patients
unable to tolerate enteral nutrition cannot be included in the studies, leaving some
experts questioning the usefulness of conducting such trials nowadays [8]. One
good- quality, single- center RCT looking at patients with expected enteral intolerance
randomized to receive either enteral or parenteral nutrition could not demonstrate
increased complications with parenteral nutrition, while in these patients enteral nutri-
tion consistently led to underfeeding, which correlated to increased mortality [9].
Enteral Nutrition
As previously mentioned, if oral feeding is not possible, it is subsequently more physi-
ological to deliver nutrients into the stomach or jejunum as it preserves the barrier
role of the gut. On the one hand, this prevents nutrients from reaching the circula-
tion too rapidly or in too high amounts, by this challenging the metabolic capacity
of the body. On the other hand, it prevents intraluminal bacteria from crossing the
gut mucosa (bacterial translocation) and contributing to the development of systemic
infections, leading to multiple organ failure [10].
When administering nutrients intravenously, this natural barrier is bypassed,
and unless closely monitored, serious metabolic and infectious complications may
develop. Indeed, this happened quite frequently in the past when the clinical impact
of common metabolic disturbances associated with total parenteral nutrition were
ignored (i.e. hyperglycemia). Therefore, overfeeding was and still is more common
in patients treated with parenteral than with enteral nutrition, and has been associ-
ated with unfavorable outcome (increased infectious and metabolic complications) in
critically ill patients [11].
When choosing the enteral route for nutrition delivery in ICU patients, two sepa-
rate desiderates should be identified: feeding the gut and feeding the patient. The first
one has been consistently proved beneficial by many RCTs and meta- analyses, while
the second one is still challenged in terms of adequacy of energy and protein delivery
(see below).
One of the common sayings in intensive care is if you dont use the gut, youll lose
it. This has been nicely shown in both animal models and humans. After 3 days of
luminal nutrient deprivation, a significant loss of intestinal mass, reduction of villous
height and crypt depth, and increased intestinal permeability could be demonstrated
[12, 13]. Moreover, a recent trial including 28 critically ill patients randomized to
receive either early (within 24 h from admission) or delayed (after 4 days) gastric
24 Grecu
feeding showed significant impairment of the intestinal absorptive capacity (as inves-
tigated for glucose absorption) in the delayed enteral nutrition group, despite similar
gastric emptying times [14]. In the delayed feeding group, an increase in the duration
of mechanical ventilation and in the length of ICU stay was shown, although mortal-
ity was similar in both groups (but the trial was not powered for this endpoint) [14].
This finding is consistent with previous trials and a meta- analysis showing that
early enteral nutrition (compared to standard practice) decreases morbidity and mor-
tality in critically ill patients [15].
From a practical perspective, feeding the gut, also named trophic or trickle feed-
ing, or minimal enteral nutrition in earlier textbooks, means continuous delivery of
small amounts of nutrition formula into the stomach or jejunum at a rate of 10 30 ml/h
starting within the first 24 to maximum 48 h from admission in the ICU, with the goal
of maintaining gut integrity and function while decreasing complications [16].
Considering the second goal of enteral nutrition, feeding the gut does not mean
we are feeding the patient as a whole, fulfilling his increased metabolic requirements
in order to support disease resolution, wound healing, and recovery. Self- evidently,
higher administration rates than the ones used for trickle feeding are required to
deliver the whole energy intake, measured or estimated. Unfortunately, gastrointes-
tinal intolerance is common in critically ill patients, directly correlates with disease
severity, and precludes full or near target enteral nutrition delivery, leading to under-
feeding. When prolonged beyond the first week after admission, underfeeding has
been shown to increase energy (and protein) debt and thus increase complications
and length of stay in critically ill patients [17, 18].
On the other hand, there might be some categories of ICU patients who can toler-
ate a limited period of underfeeding, at least in the first 5 6 days after admission, pro-
vided they are still receiving early enteral trickle feeding, as it has recently been shown
in an RCT that included overweight, predominantly female, mechanically ventilated,
single- organ (acute respiratory) failure patients [19]. Understandably, all the trials
investigating delayed feeding [14, 19] have not included previously malnourished or
very severely ill patients. The rationale behind this is these categories of patients are
either highly catabolic or have a priori reduced reserves and will therefore have worse
outcomes if not receiving both early and adequate nutritional support. Unfortunately,
this rationale is not supported by much clinical evidence thus far [4, 20, 21], and it
will be very difficult to conduct such trials from an ethical perspective.
Another common problem with enteral nutrition is the difference between pre-
scription and actual delivery. Even if an early start has been achieved through the
enteral route, when auditing the actual practice results are unanimously disappoint-
ing: only 59% of target energy and 56% of target protein intake are actually delivered
within the first 12 days of stay in the ICU, as shown in a large multicenter trial includ-
ing 2,772 patients in 167 ICUs from 21 countries [22]. Interestingly, the study also
showed that increasing energy intake by 1,000 kcal/day and protein intake by 30 g/day
resulted in a significant decrease in mortality rate and increase in ventilator- free days
How to Choose the Route 25
in patients with BMI <25 and 35 kg/m
2
. This proves that only overweight or mildly
obese patients may actually tolerate an initial period of 1 week of underfeeding, on
the condition that some amounts of enteral nutrition are delivered early [22].
The causes for prolonged hypocaloric, hypoproteic feeding commonly seen in clini-
cal practice do not only include gastrointestinal intolerance (as estimated by gastric
aspirate volume), but also the frequent interruptions in enteral nutrition delivery due
to weaning, preparation for surgery, and bedside or remote procedures [23]. A modern
approach to preventing these impediments and successfully delivering enteral nutri-
tion is to implement nurse- or dietician- driven [24] protocols in the ICU; to tolerate
higher gastric residuals [25]; or not to monitor gastric residuals volume at all [26].
Parenteral Nutrition
Parenteral nutrition is an alternative route for nutrition delivery when the enteral
route is impossible or insufficient [20]. It is reserved for patients with absolute (bowel
obstruction or ischemia, short bowel syndrome, abdominal compartment syndrome)
or relative (high- output small bowel fistulas, prolonged and severe intolerance to
enteral feeding) contraindications for enteral nutrition. However, in the latter situa-
tions, trickle feeding is sometimes possible and therefore indicated.
If parenteral nutrition is used as single feeding route, it should be started early,
within the first 24 48 h after admission to the ICU [20]. A meta- analysis showed that
early parenteral nutrition improves survival when compared to delayed enteral feed-
ing [7].
When parenteral nutrition is indicated, possible complications should be closely
monitored, and overfeeding in particular should be avoided by all means. It is impor-
tant to understand avoiding overfeeding means much more than just avoiding hyper-
glycemia, as recently shown in a large, multicenter RCT [27] (see below). Moreover,
the specific composition of parenteral solutions is of major importance, as some sub-
strates have been proven to have therapeutic roles beyond their nutritional value [28].
These substrates are discussed in detail in other chapters of this textbook.
It is therefore evident that the practice of parenteral nutrition has evolved signifi-
cantly within the last decade [3], and it will not be surprising if the results of ongoing
or future trials will be showing a similar benefit versus complication ratio for enteral
and parenteral nutrition [5].
Combined Enteral and Parenteral Nutrition
Considering the benefits of early enteral nutrition in terms of physiology, clinical out-
comes, and costs, as well as the negative influence of prolonged underfeeding due to
poor enteral tolerance in critically ill patients, it is more than reasonable to consider
26 Grecu
supplementing the enteral with parenteral route in order to achieve early target energy
and protein intake. Indeed, in practice, many ICUs throughout Europe are using this
approach more and more frequently.
Paradoxically, there is a paucity of trials in the literature looking at combined
enteral and parenteral nutrition. A meta- analysis published in 2004 [29] found no
clinical benefit and recommended against routine parenteral supplementation to
enteral nutrition when the latter is insufficient. This meta- analysis included five tri-
als, one of which was an extension of an older trial, and of the remaining four RCTs,
three had important flaws [20].
While ESPEN recommends the introduction of supplemental parenteral nutrition
(SPN) after the first 2 days from enteral feed initiation, if this is insufficient (<60%
target calories are delivered enterally) [20], ASPEN is more reluctant and recom-
mends the enteral route by all means, considering SPN only after the first week from
admission if enteral feed is not tolerated [16]. Villet et al. [17] suggested the combina-
tion allows better target calorie achievement, although in this observational trial, SPN
was introduced only after 5 days from admission.
Within the last year, three new trials investigating the usefulness of combined
enteral and parenteral nutrition were published, but with conflicting results [27, 30,
31]. It has to be mentioned, however, that there are many differences in the design
and scale of these RCTs.
A very large, two- center RCT [27] compared the ESPEN and ASPEN approaches,
as recommended in their respective guidelines [16, 20], regarding the use of SPN in
critically ill patients. Over a period of more than 3 years, the study enrolled 4,640
patients from seven different ICUs at two hospitals in Belgium. All patients received
early enteral nutrition and, in addition, patients tolerating less than 80% of require-
ments enterally were randomized to receive either early (within 48 h) SPN up to tar-
get energy goals or late initiation SPN (on the 8th day from ICU admission). The
authors showed decreased ICU and hospital stay; reduced infections, cholestasis, and
duration of mechanical ventilation; and decreased costs in the group with late initia-
tion SPN. No difference in mortality between groups was found [27].
Several criticisms have been raised to this very large interventional trial, one being
that the majority (over 60%) of patients were after cardiac surgery, a population that
rarely needs prolonged ICU stay or has an indication for artificial nutrition. Indeed,
the median length of stay in the ICU was 3 and 4 days in the late versus early ini-
tiation SPN groups, and only 48 and 51.3% of patients stayed longer than 3 days,
respectively. Another criticism is the exclusion of undernourished patients, the one
category that needs most early and full achievement of nutritional goals [4, 20]. In
addition, the study is a typical example of overfeeding, as the target energy goal was
set higher than recommendations for the acute phase, at 30 kcal/kg ideal body weight/
day. Protein delivery was lower than recommendations in both groups and, moreover,
some patients received more than 100% of target calories within the first week [27].
Interestingly, the associated negative effects attributable to overfeeding, i.e. the increase
How to Choose the Route 27
in infections rate and duration of ventilation, cholestasis, and the increased necessity
for renal replacement therapy, were observed in the early SPN initiation group despite
tight glycemic control. It should be noted that the early initiation group received sig-
nificantly more intravenous glucose in the first 2 days from ICU admission (1,200 vs.
300 kcal). Furthermore, as expected, in the late initiation group, a significantly higher
incidence of severe hypoglycemia (<40 mg/dl, 2.2 mmol/l) was noticed [27].
The other two trials investigating the benefits of SPN were smaller, but far bet-
ter designed. In the Tight Calorie Control (TICACOS) single- center RCT [30], 130
patients from a mixed ICU were randomized to receive either dietician- controlled
tight calorie intake, the target being measured by indirect calorimetry, or standard
energy intakes calculated at 25 kcal/kg preadmission body weight/day (controlled
by ward staff according to routine nutrition protocol). Both groups received enteral
nutrition and SPN. The authors showed decreased hospital mortality (28.5 vs. 48.2%,
p = 0.023) and improved 60- day survival (57.9 vs. 48.1%) in the as per protocol tight
calorie control group versus standard group, despite the fact that infections, dura-
tion of mechanical ventilation, and ICU stay were all significantly increased in the
study group [30]. The increased complications seen in the study group could again be
explained by overfeeding, as these patients received higher energy intake compared
to measured daily targets over the entire first 2 weeks after admission (fig. 1). Also in
this trial, the protein delivery, although significantly higher in the study group, did
not meet the recommended minimal intake [20].
The last study investigating a combined route for nutrition delivery has only been
published abstract form so far. It is a two- center RCT including 275 mixed surgi-
cal and medical ICU patients randomized to receive either early enteral nutrition
alone, or early enteral nutrition combined with SPN from day 4 if less than 60% of
energy needs were tolerated enterally [31]. The study found significant reduction in
new infections, duration of ventilation, and antibiotic requirements in the combined
enteral and parenteral nutrition group. These findings are contrary to the previous
two combination trials mentioned above and is the first truly positive RCT for the
benefits of a combined route. Still, a major difference from the above two trials is that
SPN was introduced only after the initial 3 days from admission and only if less than
60% energy targets were achieved by enteral route alone. In the other two trials, how-
ever, parenteral nutrition was used in combination with enteral nutrition from the
initiation of nutrition support.
It is therefore obvious that the most common mistake made when using combined
enteral and parenteral nutrition consists of overfeeding, especially in the first days after
admission when metabolic tolerance is impaired and hypercatabolism is the predominant
finding. On the other hand, it is also clear that in severe critically ill patients, requiring
longer than a few days admission in ICU, prolonged underfeeding negatively influences
the outcome. Although it is more evident today that the use of supplemental parenteral
to enteral nutrition is of benefit, avoiding prolonged underfeeding and decreasing energy
debt, it is not yet clear when the supplementation should be started exactly.
28 Grecu
Algorithm for Clinical Practice
Several algorithms for choosing the feeding route in intensive care have been proposed,
and at present most units are using protocols aiming at improving nutrition delivery.
An example of such a decision- making tree is shown in figure 2 and is derived
from two of the most quoted papers [25, 32] in the field. The indication and moment
1 2 3 4 5 6 7 8 9 10 11 12 13 14
0
500
1,000
1,500
2,000
2,500
k
c
a
l
Parenteral nutrition
Enteral nutrition
Measured nutrition
a
1 2 3 4 5 6 7 8 9 10 11 12 13 14
0
500
1,000
1,500
2,000
2,500
k
c
a
l
Parenteral nutrition
Enteral nutrition
Calculated target
Measured energy expenditure
Days b
Fig. 1. Mean daily energy targets and actual delivery (reproduced with permission from [30]).
a Study group: mean daily measured target based on indirect calorimetry compared to mean daily
energy delivered from both enteral and parenteral sources. The measured energy expenditure val-
ues were significantly different (p < 0.008) from day to day in the first 10 days. b Control group: mean
daily measured and calculated target based on weight- based formula compared to mean daily
energy delivered from both enteral and parenteral sources. The measured energy expenditure val-
ues were significantly different (p < 0.008) from day to day in the first 10 days.
How to Choose the Route 29
to start for SPN as shown in the proposed algorithm has been recently tested in an
above- mentioned RCT [31].
Conclusions
Probably the most important determinants when choosing the route are early and
adequate nutrition delivery. The most important and best defined yet is the early
On admission, is nutrition support indicated?
Expected length of ICU stay 3 days
Oral diet possible or expected to
resume within 3 days
Palliative care
Can EN be started within 24 h? Start early TPN
Reassess daily if EN possible
Start gastric feed at 20 ml/h
Increase by 20 ml/h every 6 h
Accept GRV up to 500 ml
Is EN tolerated 60% of target
delivery at 72 h?
Is minimal EN possible?
Continue EN
Increase to 100% target*
Add SPN up to 100%
energy and protein target
Reassess daily for SPN need
Decrease SPN as EN tolerance increases
Monitor for complications (infectious, metabolic)
Consider resuming oral diet
Yes
No
Yes
Yes
Yes
Yes
No
No
No
Start minimal EN
Add SPN up to 100% target
Fig. 2. Proposed algorithm for choosing the route for nutrition delivery in critically ill. EN = Enteral
nutrition; PN = parenteral nutrition; GRV = gastric residuals volume; TPN = total parenteral nutrition.
* At this point, methods to increase EN delivery could be tried (if not already) to reach 100% energy
and protein goals: prokinetics, postpyloric feeding, etc. If jejunal feeding is used, then intra-
abdominal pressure should be monitored.
30 Grecu
1 Berger MM, Chiolero RL, Pannatier A, Cayeux MC,
Tappy L: A 10- year survey of nutritional support in
a surgical ICU: 19861995. Nutrition 1997;13:
870877.
2 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 system-
atic review of the literature. Nutrition 2004;20:
843 848.
3 Singer P, Pichard C: Parenteral nutrition is not the
false route in intensive care unit. JPEN J Parenter
Enteral Nutr 2012;36:12 14.
4 Kreymann KG, Berger MM, Deutz NE, et al: ESPEN
Guidelines on Enteral Nutrition: intensive care. Clin
Nutr 2006;25:210 223.
5 NIHR Health Technology Assessment: Clinical and
cost- effectiveness of early parenteral compared with
early enteral nutritional support in critically ill
patient study (CALORIES). http://www.hta.ac.uk/
project/1760.asp.
6 Peter JV, Moran JL, Philips- Hughes J: A metaanaly-
sis of treatment outcomes of early enteral versus
early parenteral nutrition in hospitalized patients.
Crit Care Med 2005;33:213 220.
7 Simpson F, Doig GS: Parenteral vs enteral nutrition
in the critically ill patient: a meta- analysis of trials
using the intention to treat principle. Intensive Care
Med 2005;31:12 23.
8 Griffiths RD: Guidelines for nutrition in the criti-
cally ill: are we altogether or in- the- altogether?
JPEN J Parenter Enteral Nutr 2010;34:595 597.
9 Woodcock NP, Zeigler D, Palmer MD, Buckley P,
Mitchell CJ, MacFie J: Enteral versus parenteral
nutrition: a pragmatic study. Nutrition 2001;17:
1 12.
10 DeWitt RC, Kudsk KA: The guts role in metabo-
lism, mucosal barrier function and gut immunol-
ogy. Infect Dis Clin North Am 1999;13:465 481.
11 Stapleton RD, Jones N, Heyland DK: Feeding
critically ill patients: what is the optimal amount
of energy? Crit Care Med 2007;35(Suppl 9):
S535S540.
12 Levin RJ: Digestion and absorption of carbohy-
drates from molecules and membranes to humans.
Am J Clin Nutr 1994;59:690S698S.
13 Caspary WF: Physiology and pathophysiology of
intestinal absorption. Am J Clin Nutr 1992;55:
299S308S.
start: it preserves the gut function if delivered enterally and decreases mortality as
compared to late start, regardless of route (enteral or parenteral).
It is less clear, however, what adequate includes: it certainly means avoiding over-
feeding, but also prolonged underfeeding. The controversial results in clinical out-
comes of recent trials studying full target delivery versus underfeeding might be
explained by the differences in defining the optimal target in the control group and
the different populations of patients included (in terms of acute pathology, but also
previous nutritional status), and certainly request redefining adequate nutrition
more specifically, disease- related (including the stage of disease) and patient- related.
Moreover, adequate refers equally to the composition of food, as some substrates
proved to positively influence clinical outcomes (i.e. glutamine, selenium, fish oil,
etc.).
The decision- making in choosing the route is a stepwise process looking at the
possibility and adequacy of first using the oral route, then the enteral (gastric as a
first intention) and if not possible, the parenteral route. Early combination of enteral
and parenteral nutrition is a rational approach in previously malnourished or in very
severely ill patients, with a high probability of prolonged gastrointestinal intolerance.
This approach should be further investigated in well- designed and - conducted RCTs
in order to translate rationale into practice.
References
How to Choose the Route 31
14 Nguyen NQ, Besanko L, Burgstad C, et al: Delayed
enteral feeding impairs intestinal carbohydrate
absorption in critically ill patients. Crit Care Med
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15 Doig GS, Heighes PT, Simpson F, et al: Early enteral
nutrition, provided within 24 h of injury or inten-
sive care unit admission, significantly reduces mor-
tality in critically ill patients: a meta- analysis of
randomised controlled trials. Intensive Care Med
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16 McClave SA, Martindale RG, Vanek VW, et al:
Guidelines for the Provision and Assessment of
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17 Villet S, Chiolero RL, Bollmann MD, et al: Negative
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on clinical outcome in ICU patients. Clin Nutr 2005;
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18 Dvir D, Cohen J, Singer P: Computerized energy
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19 Rice TW, Mogan S, Hays MA, Bernard GR, Jensen
GL, Wheeler AP: Randomized trial of initial trophic
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sive care. Clin Nutr 2009;28:387 400.
21 Miles JM: Energy expenditure in hospitalized
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24 Soguel L, Revelly J- P, Schaller M- D, Longchamp C,
Berger MM: Energy deficit and length of stay can be
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make the difference. Crit Care Med 2012;40:
412 419.
25 Doig GS, Simpson F, Finfer S, et al: Effect of
evidence- based feeding guidelines on mortality of
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26 Poulard F, Dimet J, Martin- Lefevre L, et al: Impact
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versus late parenteral nutrition in critically ill adults.
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Control Study (TICACOS): a prospective, random-
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601 609.
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Irina Grecu, MD, PhD
Anaesthetics Department, University College Hospital
235 Euston Road, London NW1 2BU (UK)
E- Mail irina.grecu@yahoo.com
Requirements, Routes of Administration and Prescription
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 3242
How to Prescribe Nutritional Support Using
Computers
Mette M. Berger
Service of Adult Intensive Care Medicine and Burns, Lausanne University Hospital, Lausanne, Switzerland
Abstract
As other intensive care unit (ICU) therapies, nutritional support has become more complex requiring
tight supervision and monitoring. It has repeatedly been shown that despite awareness of guide-
lines and prescription of the recommended amounts of energy (25 kcal/kg), underfeeding remains a
prominent problem worldwide. In patients with prolonged stays, overfeeding has also become an
issue. This lack of fit between prescription and delivery is largely caused by the lack of visibility of the
nutritional results to nurses and clinicians. Computerized systems have brought major improve-
ments, mainly through the customization of nutrition relevant variables in a single place, making
them visible. Another important point is the possibility to change the ICU time constant to days and
weeks which is the delay relevant for nutritional changes to appear, instead of minutes and hours
which are more relevant for critical care.
Copyright 2013 S. Karger AG, Basel
The critically ill patient is admitted to the intensive care unit (ICU) to benefit from
various types of organ support, including nutritional support. Although not lifesav-
ing, nutrition has been shown to significantly influence outcome [1 3], contributing
to the success or failure of other treatments. When the quality of the support is poor,
in either under- or overfeeding or with inappropriate use of feeding techniques, the
outcome worsens.
Several process changes have been attempted to improve ICU nutritional therapy:
standardization of practice and introduction of evidence- based treatments are in the
first line of the improvements. Guidelines have improved clinical practice signifi-
cantly, but have failed to achieve optimization of energy delivery. This lack of impact
on energy delivery was confirmed in a large cluster randomized trial enrolling 1,118
patients from 27 ICUs conducted in Australia and New Zealand which compared
guideline and control ICUs: the 18- point evidence- based guideline promoted ear-
lier feeding and greater nutritional adequacy, but did not improve clinical outcomes
nor energy delivery in a significant way [4].
How to Prescribe Nutritional Support Using Computers 33
What can computers and computerized information systems (CIS) do for nutri-
tional therapy? It has been shown that CIS may be useful in several areas, espe-
cially in assisting with ancillary tasks [5] (table 1); however, it is particularly able to
ensure the safety of the nutrition process due to the possibility to monitor nutrition
therapy. Answering the question of the aim matters as there are important eco-
nomic issues behind the choice of a computer system. The installation of the most
advanced CIS linking all the beds of an ICU costs about EUR 20,000 30,000 per
bed, while a high- quality hand- held individual computer costs only around EUR
1,000.
The use of computerized systems to assist nutritional support is not new, as
one of the first papers was published in 1986 [6]. The first described aims were
to document individual patient demographic and anthropometric data, nutri-
tional disorder(s), laboratory data, nutritional support therapy, patient response
criteria, and concomitant drug therapy. Research options were immediately
identified with the constitution of data bases. In the beginning, there was a
distinction between the capacities of the portable and fixed devices [7]; however,
with iPads and other personal digital assistants, this distinction is no longer per-
tinent. But one major advantage is to finally increase the visibility of nutritional
Table 1. Computerized nutritional assistance
Function Aim
Electronic health records Patient history
Calculators of the most frequently used formulas Predictive energy requirement equations
Prescription tools with strict constraints,
e.g. computerized prescriber order entry for PN
Parenteral nutrition safety
Calculation of delivered quantities of substrates
(glucose, lipids, proteins) whatever the source,
including from drug dilution solutions
Monitoring
Customized screen providing energy balance
calculation, laboratories (urea, glucose, prealbumin,
triglycerides, ASAT, ALAT), intestinal function
(stools, gastric residuals), drugs (insulin)
Supervision at distance Integrative
monitoring of actual nutrition delivery by
the nurses/dieticians in all the beds of an ICU
Alert systems Detecting early glucose changes (hypo- or
hyperglycemia)
Clinical decision- making Integrative
Generation of reports Transmission to ward teams about nutrition
in the ICU
Access to Web- based knowledge and guidelines Self- teaching evidence- based medicine
34 Berger
therapy [8]. The text below will discuss the potential of the various forms of
computers.
Nutrition Prescription Process
Before any prescription can be made, it is essential to determine the patients met-
abolic requirements. Setting up a feeding plan with determination of the energy
and protein requirements is indeed the first step. In the vast majority of cases, the
energy targets will remain an estimation, but require knowing at least the patients
weight, height, BMI, sex, and age. While the latter two are always available, weight
and height are sometimes really hard to get only being estimated in about 30 40%
of our patients [9]. The computerized system can integrate multiple equations (table
2), including one enabling the determination of height from the knee height mea-
surement (Chumlea equation) [10], and hence the determination of the ideal body
Table 2. Examples of equations that can be integrated into computers, to assist estimation of energy
requirements
Name Formula
Chumlea equation [10] Stature- men = (2.02 KH cm) (0.04 age) + 64/19
Stature- women = (1.83 KH cm) (0.24 age) + 84/8
Harris- Benedict Men: 66 +13.8 (weight in kg) + 5 (height in cm) 6.8 (years)
Women: 655 +9.6 (weight in kg) +1.8 (height in cm) 4.7 (years)
To be used crude without a stress adjustment
Fleisch (age 2099 years) [31] Men: REE = 24 BSA (38 0.073 (age 20))
Women: REE = 24 BSA (35.5 0.064 (age 20))
BSA = weight (kg)
0.425
height (cm)
0.725
71.84
Faisy- Fagon for patients on
mechanical ventilation [32]
REE (kcal/day) = 8 body weight + 14 height + 32 V
E
+ 94
body temperature 4834
Penn State 2010 [33] For patients with BMI <30 at age 18, and for any BMI if age
<60 years:
1 REE = Mifflin(0.96) + V
E
(31) + T
max
(167) 6212
For patients with BMI 30 plus age 60 years:
2 REE = Mifflin(0.71) + V
E
(64) + T
max
(85) 3085
Mifflin St. Jeor equation for healthy people with no weight
adjustment for the obese:
REE = Wt(10) + Ht(6.25) Age(5) + Male(166) 161
KH = Knee height; REE = resting energy expenditure; V
E
= minute ventilation (l/min); BSA = body
surface area.
How to Prescribe Nutritional Support Using Computers 35
weight from tables. Other energy- predictive equations based on age, sex, weight,
and height such as the Harris- Benedict or any other preferred equation may then
be integrated. The standard weight- based equations can of course also be included,
although all these equations have shortcomings, and we now know that the target of
25 30 kcal/kg/day is too elevated in the majority of patients during the early phase
of acute disease.
The industry and several patient associations have developed applications for per-
sonal digital assistants that are easy to upload [7]: useful for the individual patient,
these applications are by definition limited to the single patient, but the use of calcu-
lators is certainly better than nothing.
Computerized Parenteral Nutrition Ordering
While enteral nutrition generally is based on industrial solutions, this is not always
the case for parenteral nutrition (PN), for which both industrial bags and individual
compounding are used [11]. Due to the multiple possible errors involved with the lat-
ter, computerized prescription order entry is advocated for PN, and is recommended
by the nutrition societies ASPEN [12] and ESPEN. These systems improve safety [13],
particularly in the pediatric context which is the most heavily dependent on individu-
alized prescription.
Using the widely available Microsoft Excel application is an alternative to the
complex CIS, enabling the creation of a computer- based order form that auto-
matically calculates doses, infusion rates, and the osmolarity of the formulation.
A section of the sheet may summarize the nutrient content of the prescribed PN
formulation [13]. Multiple checkpoints in the process enable the identification and
resolution of errors. These systems also have the enormous advantage of forcing
collaboration between physicians and pharmacists, the latter checking any issues
with PN (such as compatibility, dosages) and, if necessary, contact the prescriber
to correct the order. Drawbacks of any computerized prescription order entry is
the need for constant updating of the system (product shortages, new prepara-
tions), changes in practice, and to educate the prescribers regarding the logic and
warnings of the system [13]; however, these limitations apply to any computerized
system.
Nutritional Monitoring
Monitoring nutritional support on line is at least as important as prescription.
Indeed, as shown by a large international survey including 2,772 mechanically
ventilated patients [1], the patients were only receiving 14 kcal/kg/day despite
an adequate mean prescription of 24 kcal/kg/day. This low mean level of energy
36 Berger
intake seems to correspond to a sort of international standard. This is so because
the paper- based monitoring sheets do not show the nurses and physicians how
much of the feeds is really delivered and does not enable delivering it in a goal-
directed way. Indeed, our monitors enable the visualization of arterial blood pres-
sure and oxygen saturation, but not of the metabolic variables. While goal- directed
therapy has become a standard for other ICU therapies, this remains nearly
impossible for nutrition in ICUs without CIS. The latter can compact the daily
data into another time frame more useful for nutrition, i.e. days and sometimes
weeks, which is different from the requirements of respiratory and cardiovascular
monitoring.
Having computerized our ICU in 1999, we investigated the impact of this change
on the quality of nutritional support by comparing nutrient delivery before and after
CIS implementation [8]. Computerization was associated with several improve-
ments in all patient categories. This was mainly due to forcing standardization of
nutritional care with a unified protocol, but also through the impact of the ability
of the nurses to monitor the ongoing feeding and correct feeding rates if the target
was not achieved. The feeding process was finally made visible (fig. 1): information
regarding the prescribed energy target, the energy delivery including the route its
completion or not (% of target delivered), the daily substrate delivery, the presence
or not of stools and gastric residuals, and the type of feeding are grouped on one
screen. In the above study [8], energy delivery was particularly increased in burn
patients, becoming significantly closer to target, with better adaptation of feeding
Fig. 1. Detail of the energy and substrate monitoring over 2 days: every column gives the data of
the last 24 hours. The lower box shows how many grams of proteins, glucose, or fat were delivered
on that day.
How to Prescribe Nutritional Support Using Computers 37
rates as any delay in feeding was visible on the screen, resulting in a 5% decrease in
weight loss after computerization. CIS also decreased significantly the time devoted
to writing and computation, which enables the nurses to increase the time dedicated
to the patients.
More recently, we showed that the supervision and intervention tasks of the ICU
dietician are facilitated by the system. Using the CIS during her morning office
round to detect problems in the 32 ICU beds, she has become able to address the
issues in those patients in trouble, without having to physically visit every patient:
this process results in early intervention and improved energy delivery [9]. Again,
it shows the importance of visibility and nutrition therapy based on standardized
protocols.
Substrate Monitoring
Substrate delivery requires specific attention: lipid protein and glucose delivery may
all be too high or too low, depending on the industrial solutions used in the ICU and
the volumes really delivered the computerized system directly calculates the actual
delivery.
Fat
The fat proportion of the energy intake, and the amount of saturated fatty acids
should be limited in all ICU patients as in the general population [14]. Total lipid
amounts and particularly those delivered as long- chain triglycerides should be lim-
ited to less than 1.5 g/day [15, 16]. Large doses of fat have been shown to reduce the
immune response among other side effects [16]. Recently, CIS have made us aware
of fat being delivered in significant amounts (20 30 g/day) coming with the sedative
propofol [8, 17]. As fat oxidation delivers 9 kcal/g, the integration of the sedative-
related fat delivery (nonnutritional energy) into the energy calculations is important
to avoid overfeeding. Figure 1 shows the amounts of fat that were provided in a 55- kg
patient with encephalitis by propofol (4,500 5,000 mg/day) and by the enteral feed:
the quantities are immediately visible on the dedicated CIS screen, facilitating aware-
ness about the significant fat delivery. In this patient, who had a calorimetry- validated
energy target of 1,500, the 23 g of fat from propofol (200 kcal) resulted in overfeeding
(120% of target), or alternatively would have required reducing the balanced nutri-
tional intake to 1,300 kcal which would have resulted in a drastic reduction of protein
intake below requirements (70 g/day, i.e. 1.3 g/kg/day). This indeed happened later in
the long ICU stay as shown in figure 2.
Protein
Protein delivery has not yet been given enough attention. Achieving 1.2 1.3 g/day of
proteins has recently been shown to be associated with improved outcome. A group
38 Berger
from the Netherlands showed that the computerized follow- up of feeding resulted
in the progressive delivery of larger amounts of nutrients [18], particularly proteins
[19].
Figure 2 shows the evolution of the same patient over 10 months, whose initial
weight was 55 kg. Despite indirect calorimetry data, the prescribed energy target
was reduced after 6 months based on good prealbumin values and continued heavy
sedation, although the patient was agitated and had started moving intensely: preal-
bumin dropped abruptly while the weight further decreased to 38.9 kg (BMI 15.2).
The patient developed nosocomial pneumonia: the prescribed energy was increased
in response to bedsores to 1,800 kcal (i.e. 45 kcal/kg) and to 1.5 g/kg/day of proteins
1,900
BMI 15.2
Body weight
Energy target
Prealbumin g/l
At 8 months
Protein + energy
1,800
1,700
1,600
1,500
1,400
1,300
1,200
55
50
45
40
35
0.40
0.38
0.36
0.34
0.32
0.30
0.28
0.26
0.24
0.22
0.20
0.18
0.16
0.14
0.12
0.10
0.08
0.06
Fig. 2. Evolution over 11 months of a 23- year- old female patient treated for encephalitis: upper seg-
ment shows the evolution of the prescribed energy target which varied between 1,300 and 1,800
kcal/day, the evolution of body weight with a low at 38.9 kcal on the 8th month, and the prealbumin
levels. At the lowest prealbumin value (at 8 months, arrow), the protein intake was increased from
50 g/day to 80 g/day and energy delivery from 1400 to 1800 kcal/day.
How to Prescribe Nutritional Support Using Computers 39
under supervision of liver tests and insulin resistance. Slowly the patient regained
weight and normalized her prealbumin values, showing the importance of watching
both energy and protein delivery.
Glucose
The maximal oxidizing capacity of glucose (5 mg/kg/h) should not be exceeded, and
CIS, by integrating in the daily count of glucose used for drug dilution and nutrition,
enables this monitoring. Glucose control has become an important objective for sev-
eral reasons [20], but tight glucose control has proven difficult to achieve in most gen-
eral ICUs, causing a worrying incidence of hypoglycemic events [21]. Although there
is no definitive knowledge about the optimal glycemic target, severe hyperglycemia
(>10 mmol/l) and hypoglycemia (<2 mmol/l) are recognized as life- threatening events.
Underfeeding favors both hypoglycemic events and glycemic variability, which have
been identified as major determinants of mortality [22, 23]. Computerized systems
have become efficient in limiting the occurrence of glycemic extremes and the glyce-
mic variability [24, 25]. A recent editorial heralded the importance of responding to
glycemia in a timely manner [23]. The incidence of hypoglycemia can be reduced to
0.1% of all measurements as shown by a survey including 4,588 ICU patients treated
with a computer- based glucose stabilizer program [25]: the likeliest reason for these
good results was the early warning by the system. Most of the reported computer
systems are not integrated in any other CIS [26], which reduces the power of the pro-
tocols: data integration by means of CIS increases the efficiency. The development of
a computerized decision- support tool for intravenous insulin dosing [27] results in a
significant improvement in the likelihood (2.28 times) of having blood glucose levels
<150 mg/dl (p < 0.001).
Glycemic control during the initiation of PN may be difficult. A study including
23 critically ill patients showed that rapid initiation of PN using a step- up approach
coupled with computerized glucose control resulted in achieving a 1 kcal/kg/h intake
within 24 h while maintaining adequate glycemic control [28]. Data from the Swiss
SPN trial confirm that CIS, using combined enteral and parenteral feeding under CIS
supervision does not compromise glucose control [29].
Research and Quality Control
The creation of large databases enables testing various hypotheses: this specificity of
computers has generated a large number of studies using either a before and after
design to test the impact of a new treatment or method, or retrospective studies to
generate background to future interventional studies. The paper by Alberda et al. [1]
was a hypothesis- generating study, while the study by Soguel et al. [9] was a quality
control study checking the impact of two sequential interventions. CIS also reduces
the workload involved in case report generation.
40 Berger
1 Alberda C, Gramlich L, Jones N, et al: The relation-
ship between nutritional intake and clinical out-
comes in critically ill patients: results of an
international multicenter observational study.
Intensive Care Med 2009;35:1728 1737.
2 Artinian V, Krayem H, DiGiovine B: Effects of early
enteral feeding on the outcome of critically ill
mechanically ventilated medical patients. Chest
2006;129:960 967.
By offering data extraction possibility, the quality control process is facilitated.
This is not the only value of CIS: the most versatile systems enable extraction over
defined periods of time of parameters such as all glycemias, all hypoglycemic events,
all negative energy balances, daily doses of insulin, and/or other indicators consid-
ered important. Automated extractions enable the continuous quality control, feed-
back loops, and adequate follow- up of adherence to guidelines.
Maintaining Up- to- Date Knowledge
Finally, computers have an important place in keeping healthcare professionals
well informed. As in other fields, there is a rapid evolution of nutrition knowledge:
professionals are faced with the necessity of being able to rapidly find information
to answer clinical questions that arise during daily practice. Information- seeking
skills must be developed in order to find information from the Internet, as well as
in the professional literature. Such skills include the ability to formulate a search
strategy that limits extraneous results as much as possible, yet ensuring that rel-
evant results are not missed, as well as skills to assess the quality of the information
found on the Web [30]. Indeed, it may be very difficult to assess the credibility,
content, disclosures of the site, the quality of the links, the design (user friendli-
ness), the interactivity of the site, and the caveats regarding the provided informa-
tion, which may be present or not. A wild search on the Web is worthless. The sites
of the professional societies (ASPEN, ESPEN, etc.) are the safest regarding these
aspects.
Conclusion
Computerized systems have changed the ICU life, enabling an integrative access to
monitoring. They have finally made nutritional therapy and metabolic monitor-
ing visible. Combined with standardized feeding protocols, and customized time
intervals that are adapted to the metabolic response, i.e. days, with all data related
to the response to feeding, these systems enable major progress in ICU nutrition
therapy.
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Prof. Mette M. Berger
Service of Adult Intensive Care Medicine and Burns
Lausanne University Hospital (CHUV BH- 08.612)
Rue du Bugnon 46
CH 1011 Lausanne (Switzerland)
Tel. +41 21 31 42 095, E- Mail Mette.Berger@chuv.ch
Requirements, Routes of Administration and Prescription
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 4349
Oral Feeding
Ana Alvrez- Falcn
a
Sergio Ruiz- Santana
b
a
Dietetic Department and
b
Intensive Care Unit, Hospital Universitario de Gran Canaria Dr Negrn,
Las Palmas de Gran Canaria, Spain
Abstract
Early nutrition can help to improve energy and protein intake and decrease the negative impact of
the metabolic response to surgery. A key goal is to identify patients who exhibit increased respira-
tion risk before beginning oral alimentation. Once a simple bedside 3- oz (90 ml) challenge, or early
intervention in the oral care, administered by a trained provider is passed, specific diet recommen-
dations can be made safely and confidently without the need for further objective dysphagia test-
ing. Gastrointestinal motility disorders occur as part of the pathophysiology of diseases and critical
illness, or are a result of medication therapies or enteral feeding complications. Inadequate energy
intake in the first 7 days following extubation have recently been described. It would be highly ben-
eficial to determine when it is best to initiate timely oral alimentation for recovering extubated
intensive care unit (ICU) and more specifically surgical ICU patients to support the maintenance and
rebuilding of lean body mass, maintain hydration, and permit the ingestion of oral medications. In a
cross- sectional multicenter study conducted in 18 Spanish ICUs, within the scope of the 2007
European Nutrition Day, only 95 of 348 investigated patients (27.3%) received oral nutritional sup-
port. Constipation and diarrhea were common adverse effects. Unexpectedly, however, constipation
episodes were more frequent than diarrhea in the patients not receiving oral nutritional support.
Copyright 2013 S. Karger AG, Basel
Traditional nutritional management of patients undergoing major abdominal sur-
gery has involved a period of nil by mouth with nasogastric decompression, fol-
lowed by a clear liquid diet that gradually progresses to regular food on the fourth
or fifth postoperative day. The Enhanced Recovery after Surgery (ERAS) program,
with early oral feeding as one of the key elements, recommends having exten-
sive preoperative patient information, avoiding nasogastric decompression tubes,
midthoracic epidural anesthesia/analgesia with low doses of opioids, avoiding fluid
overload, and multimodal management of postoperative nausea and vomiting
(5- HT3- antagonist and/or dehydrobenzperidol and/or dexamethasone). Patients
should start drinking within 4 h after surgery and are allowed to eat normal food on
the first postoperative day. This was developed by 26 Dutch hospitals in 2006 and
44 Alvrez- Falcn Ruiz- Santana
proved that the feasibility of early oral nutrition in most of the patients stresses the
necessity of abolishing postoperative starvation. Patients can eat and drink imme-
diately after the operation. Structured PONV (postoperative nausea and vomiting)
management is an important prerequisite for a successful early start of nutrition
after abdominal surgery [1].
Identification of the Problem
It is necessary to identify patients who exhibit increased aspiration risk. For this, we
can use the techniques detailed below.
3- oz (90 ml) Water- Swallowing Test
This task requires dinking 3 oz of water directly from a cup or via a straw, either
assisted or independently, without interruption [2]. Criteria for failure are the
inability to drink the entire volume, interrupted drinking, or coughing during
drinking or immediately after completion of the test. If a patient fails the 3- oz
water- swallow challenge, it should be repeated within 24 h because intensive care
unit (ICU) and step- down unit patients often demonstrate rapid improvement
in swallowing function. However, if the challenge is passed, cognitive limitations
and dentition status determine specific oral diet recommendations and the abil-
ity to safely drink thin liquid and eat an oral diet 12 24 h after passing the 3- oz
challenge.
The recommended diets span thin liquids with puree and food with a soft or regu-
lar consistency. It is not necessary to modify thin liquids with thickening agents to
nectar or honey consistencies to promote safe ingestion.
Factors such as premorbid feeding status and ability, cognitive status, cooperative-
ness and levels of consciousness, gross oral motor functioning, respiratory muscle
function and endurance, and posture limitations need to be assessed before using a
3- oz water swallow challenge. This test is not recommended for use in patients with
head and neck malignancy or those who require a tracheotomy tube.
Endoscopy or Fluoroscopy Test
This is recommended for patients with head and neck malignancy, a tracheotomy
tube (e.g. for airway maintenance), ongoing mechanical ventilation, and pulmo-
nary toilet. Silent aspirations occur more frequently because of laryngeal desen-
sitization from chronic aspiration of secretions and combined chemoradiation
therapy.
Early Intervention
Patients with diminished consciousness can participate in early intervention pro-
grams, like the one in the study by Takahata et al. [3] in patients with intracerebral
ICU Oral Feeding 45
hemorrhage. It consists of oral care (5 min), which includes teeth brushing and rins-
ing with 100 ml of water removed by suction to prevent the patient from accidentally
swallowing it and while the patient is in a lateral semi- sitting position. Stimulation of
the mouth, tongue, and oral cavity is also performed, at least 3 times daily. To initiate
oral feeding, the diet must have an appropriate texture (jelly or puree) and the patient
has to be fed in a semi- sitting way with the chin tucked position and monitoring of
oxygen levels.
The Functional Oral Intake Scale (FOIS) developed by Crary et al. [4] is
applicable to patients with impaired consciousness and evaluates swallowing based
on nutritional status and diet texture. It is a simple scale with a high intrarate
agreement and sensitivity. It has been validated by comparison with the Mann
Assessment of Swallowing Ability and video- fluoroscopic swallowing evalua-
tion. Patients free of nutritional supplementation (FOIS score 4 7) are able to eat
(table 1).
Intervention
The early intervention program is based on a behavioral intervention coordinated by
a team, and typically requires several months for all of the team members to attain
enough experience.
Nutrition Risk Screening of Critically Ill Patients
Determining baseline nutrition status is the first step in the development of a nutrition
plan. Visceral proteins are of little value in the nutrition assessment of the critically ill
patient. The Nutritional Risk Screening (NRS- 2002) tool is a quick and efficient way
of estimating nutrition status. The most important step in preventing refeeding syn-
drome is the identification of patients at risk for disorders. Nutritional intake must
be monitored weekly by members of a nutritional support team to ensure adequate
nutrition during the patients hospital stays [5].
Table 1. Functional Oral Intake Scale (FOIS)
Level 1: Nothing by mouth
Level 2: Tube- dependent with minimal attempts of food or liquid
Level 3: Tube- dependent with consistent oral intake of food or liquid
Level 4: Total oral diet of a single consistency
Level 5: Total oral diet with multiple consistencies, but requiring special preparation or
compensations
Level 6: Total oral diet with multiple consistencies without special preparation, but with specific
food limitations
Level 7: Total oral diet with no restrictions
46 Alvrez- Falcn Ruiz- Santana
Nutrition Assessment of Critically Ill Patients
It is appropriate to consider any patient to be at nutritional risk if staying more than
2 days in the ICU without near normal oral intake, and it is appropriate to critically
review the individual nutrition- related factors given that no ICU- specific scoring sys-
tem including nutrition- related indicators exists [6]. An individuals nutrition his-
tory is the first step in risk assessment and has three key indicators: (1) actual BMI,
(2) recent (3 6 months) weight loss, and (3) recent decrease in nutrient intake. A
valid BMI is difficult to obtain without the individuals measurement of height and
weight.
Energy and Nitrogen Requirement
In acute and chronic disease, the resting metabolic rate is elevated above the val-
ues calculated by the Harris- Benedict equations. Therefore, 25 kcal/g of the ideal
body weight furnish an approximate estimate of daily energy expenditure and
requirements, and requirements may approach 30 kcal/kg of the ideal body weight
under conditions of severe stress. To avoid the risk of overfeeding, the calorie and
nitrogen requirement should be calculated with indirect calorimetry or based on
unusual body weight. Moreover, in such cachectic patients, care should be taken to
increase the amount of calories and protein slowly to prevent refeeding syndrome
[7].
It is recommended to maintain the glucose- fat calorie ratio at 60:40 or even 70:30
of the nonprotein calories. When fluids restriction is indicated at 50:50, the ratio is
accepted.
In illness/stressed conditions, a daily nitrogen delivery equivalent to a protein
intake of 0.8 1.5 g/kg ideal body weight (or approx. 20% of total energy requirements)
is generally effective to limit nitrogen loss during metabolic stress and increasing in
recovery when a normal anabolic state has returned [7, 8].
Types of Diets Used
The type of food must have the same texture, and foods containing filaments or
lumps or which have a sticky consistency should be avoided. Gelatine (which is ideal
to hydrate), puree fruits and enriched vegetables, liquid or solid yogurts (taking care
of removing the liquid that contains the solid yogurt), fruit pieces, or cereals are good
foods to use. The introduction of yogurt can improve the intestinal tract after large
amounts of antibiotics. Pureed vegetables with meat or fish, pureed fruit mixed with
yogurt, custard, yogurt or jellies are also recommended.
Inadequate energy intake in the first 7 days following extubation independent of
age, nutritional status, severity of illness, location in the hospital, ICU and hospital
length of stay, and days on mechanical ventilation have recently been described [9].
The use of therapeutic dietary restriction may also increase the risk of malnutrition
in extubated patients. Moreover, prescription of therapeutic diets (e.g. low sodium or
low fat), which by definition restricts single or multiple nutrients, is counterintuitive
ICU Oral Feeding 47
for these patients with minimal intake. There is no common recommended guideline
or protocol on how to act with oral feeding in the ICU, in particular in the prevention
of malnutrition or refeeding, and the value of having an expert, such as a dietitian,
focusing on the nutritional needs of each individual patient has yet to be understood.
Nutritional intake of these patients must be monitored weekly by members of a nutri-
tional support team to ensure adequate nutrition during the patients hospital stay
after extubation from mechanical ventilation [9 13].
Obstacles
Gastrointestinal Motility Disorders in Critically Ill Patients
Motility disorders may involve any part of the gastrointestinal tract, including the
esophagus, stomach, small intestine, and colon. The symptoms for these disorders
commonly include delayed gastric emptying, constipation, adynamic ileus, and
diarrhea.
Delayed gastric emptying is common in critically ill patients, especially in patients
who are mechanically ventilated or have suffered a traumatic brain injury. Fluid and
electrolyte disturbances are common in ICU patients and can have profound effects
on gastrointestinal motility.
Constipation is a symptom of underlying pathologies and has been reported in as
many as 83% of critically ill patients [14]. Common medications used in the ICU that
can decrease gastrointestinal motility and cause constipation include sedatives and
opioid analgesics.
Medications that commonly cause diarrhea include antibiotics, laxatives, oral
magnesium, phosphate supplements, antacids, prokinetic agents, and hyperosmolar
or sorbitol- containing oral liquid medications.
The Spanish Experience
A Spanish Study
A cross- sectional and multicenter study was conducted in 18 Spanish ICUs within the
scope of the 2007 European Nutrition Day (unpubl. data). In this study, among the 348
investigated patients, 95 (27.3%) received oral nutritional support, 64 (18.4%) paren-
teral nutrition, 122 (35.1%) enteral nutrition, and 15 (4.3%) combined enteral and
parenteral nutrition. No nutritional support was given to the remaining 52 patients
(14.9%). Oral nutritional support was more frequent in nonventilated patients (56.3
vs. 2.7%) and both parenteral (23.9 vs. 11.9%) and enteral nutrition (52.7 vs. 14.4%) in
ventilated patients than in those breathing spontaneously. Constipation and diarrhea
were common adverse effects of enteral nutrition. Unexpectedly, however, constipa-
tion episodes were 3.5 times more frequent than diarrhea episodes (34.3 vs. 9.7%) in
48 Alvrez- Falcn Ruiz- Santana
1 Maessen JM, Hoff C, Jottard K, et al: To eat or not to
eat: facilitating early oral intake after elective colonic
surgery in the Netherlands. Clin Nutr 2009;28:
29 33.
2 Leder SB, Suiter DM, Warner HL, Kaplan LJ:
Initiating safe oral feeding in critically iII intensive
care and step- down unit patients based on passing a
3- ounce (90 millilitres) water swallow challenge.
J Trauma 2011;70:1203 1207.
3 Takahata H, Tsutsumi K, Baba H, Nagata I, Yonekura
M: Early intervention to promote oral feeding in
patients with intracerebral haemorrhage: a retro-
spective cohort study. BMC Neurology 2011;11:6.
4 Crary MA, Mann GD, Groher ME: Initial psycho-
metric assessment of a functional oral intake scale
for dysphagia in stroke patients. Arch Phys Med
Rehabil 2005;86:1516 1520.
5 Miller KR, Kiraly RN, Lowen CC, Martindale RG,
McClave SA: CAN WE FEED? A mnemonic to
merge nutrition and intensive care assessment of
the critically ill patient. JPEN J Parenter Enteral
Nutr 2011;35:643 659.
6 Hiesmayr M: Nutrition risk assessment in the ICU.
Curr Opin Nutr Metab Care 2012;15:174 180.
7 Gianotti L, Braga M: Revising concepts of artificial
nutrition in contemporary surgery: from energy
and nitrogen to immuno- metabolic support. Nutr
Hosp 2011;26:56 57.
8 Turner P: Providing optimal nutritional support on
the intensive care unit: key challenges and practical
solutions. Proc Nutr Soc 2010;69:574 581.
9 Peterson SJ, Tsai AA, Scala CM, Sowa DC, Sheean
PM, Braunschweig CL: Adequacy of oral intake in
critically ill patients 1 week after extubation. J Am
Diet Assoc 2010;110:427 433.
the patients not receiving oral nutritional support. As anticipated, patients fed exclu-
sively with oral nutrition were significantly less severely ill compared to those not fed
by oral nutrition (table 2).
References
Table 2. Oral vs. no oral nutritional support: clinical data and complications (unpubl. data)
Variable Oral nutritional support p
yes (n = 95) no (n = 253)
Male/female ratio, % 80.0/20.0 65.4/34.6 < 0.012
Age, years, mean (SD) 61.8 (16.6) 60.5 (17.1) < 0.532
Weight, kg, mean (SD) 74.9 (10.8) 74.7 (15.7) < 0.906
Height, cm, mean (SD) 168 (7.8) 167 (9.1) < 0.436
BMI, mean (SD) 26.6 (3.2) 26.6 (4.9) < 0.841
Emergency/elective patients, % 86.3/13.7 75.6/24.4 < 0.031
Surgical/medical patients, % 21.1/78.9 42.7/57.3 < 0.001
Glasgow coma score, median (IQR) 15 (1415) 14 (915) < 0.001
SAPS II score, median (IQR) 33 (2142) 40 (2945) < 0.001
SOFA score, median (IQR) 2 (13) 5 (39) < 0.001
Bowel movements, % < 0.022
Constipation (>3 days) 20.8 34.3
Diarrhea 2.1 9.7
Normal 77.1 56.0
ICU Oral Feeding 49
10 Peterson SJ, Sheean PM, Braunschweig CL: Orally
fed patients are at high risk of calorie and protein
deficit in the ICU. Curr Opin Clin Nutr Metab Care
2011;14:182 185.
11 Ferrie S, Alman- Farinelli M: Development as a tool
to measure dieticians involvement in the intensive
care setting. Nutr Clin Pract 2011;26:330 338.
12 Ferrie S, Alman- Farinelli M: Defining and evaluat-
ing the role of dieticians in intensive care: State of
play. e- SPEN Eur e- Journal Clin Nutr Metab 2011;6:
e121 e125.
13 Minig L, Biffi R, Zanagnolo V, et al: Early oral ver-
sus traditional postoperative feeding in gyneco-
logic patients undergoing intestinal resection: a
randomized controlled trial. Ann Surg Oncol 2009;
16:1660 1668.
14 Btaiche Imad F, Lingtak- Neander C, Pleva M, Kraft
MD: Critical illness, gastrointestinal complications,
and medication therapy during enteral feeding in
critically ill adults patients. Nutr Clin Pract 2010;
25:32 49.
Sergio Ruiz- Santana, MD, PhD
Hospital Universitario de Gran Canaria Dr Negrn
ES 35010 Las Palmas de Gran Canaria, Canary Islands (Spain)
Tel. +34 928 450673, E- Mail sruisan@gobiernodecanarias.org
Requirements, Routes of Administration and Prescription
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 5058
Enteral Nutrition
Ronit Anbar
Institute for Nutrition Research and Nutrition Unit, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
Abstract
Nutritional support is an integral part of the treatment of the critically ill patient. Enteral feeding
is viewed as the first line of feeding of the intensive care unit (ICU) patient and has many benefits
in maintaining the functionality of the intestine. When we consider the nutritional support of the
ICU patient, we first define the calorie- protein target, and then then determine the route of feed-
ing, timing for starting the feeding, and the most appropriate formula. Usually enteral feeding is
started in the early stages of ICU hospitalization, after 24 48 h, in order to maintain the gut bar-
rier functionality and support the immune system response. The patient population in the ICU is
very heterogenic and the appropriate formula should be chosen with care. A right formula could
positively affect clinical outcomes. Many available formulas, including formulas enriched with
specific pharmaconutrients such as arginine, glutamine, fish oil, and antioxidants have proven to
be beneficial. In this chapter, we will discuss the known properties and the different
approaches of various formulas according to clinical conditions and will also estimate the
possible complications of enteral feeding. Copyright 2013 S. Karger AG, Basel
Enteral nutritional support provides nutrients using solutions fed into the gastrointes-
tinal tract. If oral feeding is not possible, enteral nutrition is the first feeding line for
critically ill patients. It supports the structural and functional integrity of the intes-
tine, preventing increased gut permeability and associated bacterial translocation.
The European Society for Clinical Nutrition and Metabolism (ESPEN) recom-
mends that all patients who are not expected to be on a full oral diet within 3 days
should receive enteral nutrition [1]. The European [1], American [2], and Canadian
[3] guidelines recommend that ventilated, hemodynamically stable patients, with a
functioning digestive system, begin enteral nutrition 24 48 h after admission to the
intensive care unit (ICU).
These recommendations are based on several studies and reviews. The review of
Marik and Zaloga [4], covering 753 ICU patients, revealed a significant decrease in
infections and duration of hospitalization for patients that received early enteral feed-
ing. A meta- analysis by Doig et al. [5] included six studies that compared patients that
received enteral feeding within 24 h with patients that received late enteral feeding.
Enteral Nutrition 51
These studies covered 234 trauma, medical and surgical ventilated, burn, and pan-
creatitis patients, and demonstrated a significant decrease in mortality and incidents
of pneumonia. The authors, however, did state that the results are limited due to the
small study population and study methodology, requiring further studies.
Determination of Nutritional Goals
Before enteral feeding can be commenced, the nutritional goals need to be deter-
mined. It is recommended to set the nutritional goals according to the energy expen-
diture as it is measured by indirect calorimetry. This is considered the most accurate
way to measure energy expenditure. When measurement is not feasible, the nutri-
tional goals should be calculated as 25 30 kcal/kg or by using equations for estimat-
ing resting energy expenditure [1, 2, 6].
In critically ill patients, protein has a central role in wound healing, supporting the
immune system, and maintenance of lean body mass; however, it is difficult to deter-
mine the required protein levels in this condition. In most cases, the protein needs are
higher relative to the energy needs and are calculated as 1.2 2 g/kg or as a proportion
of 1:100 to 1:70 nonprotein kcal per gram of nitrogen [2]. This is the reason why many
of the standard formulas do not meet protein requirements and it is recommended to
consider the use of high- protein solutions or supplementation with protein. An obser-
vational study published recently by Weijs et al. [7] demonstrated that optimal energetic
nutritional support using calorimetric measurements combined with protein support
of at least 1.2 g/kg protein is linked with a reduction of 28- day mortality by 50%.
Recent publications support hypocaloric high- protein nutritional support for
obese patients that are hospitalized in the ICU [8, 9]. The purpose of this treatment
is to eliminate overfeeding and its consequences, including hyperglycemia, and to
enable anabolism while maintaining free fat mass, loss of fat mass, and improve insu-
lin sensitivity. Recent expert opinion for obese patients with BMI >40 recommend
to provide 60 70% of the energy requirements that are determined using indirect
calorimetric measurements or calculated by equations. Another option is to provide
11 14 kcal/actual body weight or 22 25 kcal/kg ideal body weight/day [2, 9]. From
a protein perspective, for patients suffering from obesity with BMI <40, the recom-
mendation is to provide more than 2 g/kg/day; for morbidly obese patients with BMI
>40, it is recommended to supply more than 2.5 g/kg ideal body weight of protein and
to monitor UUN levels [9].
Monitoring Tolerance of Enteral Feeding
In the ICU, an early enteral feeding meeting the nutritional goals is the proposed
strategy. However, many patients suffer from gastric dysmotility. It is estimated that
52 Anbar
7 47% [10] of patients in the ICU suffer from gastrointestinal motility problems.
Motility problems are attributed to several causes including the current illness, comor-
bidity, age, and medication such as opiates or norepinephrine. In clinical practice,
gastric residual volume (GRV) is viewed as the most common indicator of tolerance
for enteral feeding. This method has many limitations and studies have not found a
correlation between GRV and pneumonia resulting from aspirations [10]. McClave
et al. [11] found that when fed enterally, patients with high GRV and patients with
relatively low GRV had a similar rate of complications.
GRV can be used in combination with other indicators such as vomiting and ino-
tropic support. It is advised that monitoring the trend of several GRV measurements
over time is a powerful indicator, much more valuable than a single GRV measurement
[10, 11]. There is a lack of standard GRV levels. According to the American Society
for Parenteral and Enteral Nutrition (ASPEN), when GRV levels are 200 500 ml,
and with the absence of other indicators for intolerance of feeding, enteral feeding
should not be stopped [2].
One of the recommended approaches to tackle motility problems is the use of
prokinetic medication, the most common being metoclopramide and erythromycin
administered according to protocols. Another approach is the transition to postpylo-
ric feeding. This kind of feeding, directly to the small bowel, bypasses the stomach,
and enables reaching nutritional goals faster and eliminates the need for parenteral
feeding. Direct feeding to the small bowel does not cause special complications. The
main disadvantage relates to the difficulty in placement. Several studies and meta-
analysis have questioned the advantages of postpyloric feeding in the ICU. A small
number of studies demonstrated that postpyloric feeding benefit by reducing gas-
troesophageal reflux and rate of aspirations. A meta- analysis published by Ho et al.
[12] covering 11 studies of 637 ICU patients did not demonstrate an advantage in the
clinical outcome of patients fed directly to the small bowel concerning mortality rate,
duration of hospitalization, and rate of pneumonia and aspiration.
The common nutritional protocols of the ICU most often recommend a transit to
postpyloric feeding in patients with high risk of aspiration and with patients suffering
from intolerance to nasogastric feeding [2].
Selecting the Appropriate Enteral Solution
After deciding to start enteral feeding and after determining the nutritional goals,
the most appropriate feeding solution must be selected. Many formulas are readily
available for enteral feeding. These can be divided into two main categories: stan-
dard formulas and disease- specific formulas. Standard formulas reflect the require-
ments for macro- and micronutrients for a healthy population. Most standard
formulas contain whole protein, lipids in the form of long- chain triglycerides, and
fiber. However, nonfiber- containing formulas with otherwise similar compositions
Enteral Nutrition 53
also exist [13]. Disease- specific formulas are complete nutritional solutions with
specific macro- and micronutrient compositions designed to the needs of a spe-
cific disease and/or digestive or metabolic disorder [13]. Some of these solutions
are supplemented with pharmaconutrients that may help reduce oxidative damage
to cells and tissues, modulate inflammation, and enhance beneficial stress response
[14].
When choosing the appropriate feeding formula, it is recommended to first assess
the medical and nutritional state of the patient, and then to determine whether there
is an advantage in using a specialized immune- modulating formula. It is important
to note that this group of formulas includes a variety of products that differ one from
another in both composition (different types, numbers, and concentrations of sup-
plemented nutrients) and physiologic actions. The macronutrients belonging to this
group include glutamine, arginine, omega- 3 fatty acids, antioxidants (such as the vita-
mins and minerals: selenium; zinc; and vitamins A, C, E), and nucleotides. Due to
the great heterogeneity of studied patient populations and the different formulas and
combination of immunonutrition components, care must be used when projecting
this information to the different groups of patients in the ICU. Figure 1 shows a deci-
sion tree that describes and helps with the selection of the most appropriate formula
for ICU patients.
SBS/
malabsorption
ICU patient
Intact GI tract?
Can tolerate enteral feeding?
Yes,
begin enteral feeding
No,
parenteral nutrition
with enteral trophic feeding
ARDS/
ALI
Anuric/
fuid restriction
Elective surgical
upper GI/
trauma/burns
No special needs
Enteral formula enriched
with omega-3 fatty acids
and antioxidants
Polypeptide-
based formula
Calorie-dense formula Immune-modulating
enteral formulation
Standard high protein
formula/standard
formula supplemented
with protein
Fig. 1. Selecting the most appropriate enteral formula for the ICU patient (adapted from [14]).
54 Anbar
Glutamine
When in a state of catabolic stress, the glutamine stored in muscle tissue is depleted
and it becomes conditionally essential. Several beneficial properties are associated
with glutamine, including it being an antioxidant, promoting production of heat
shock proteins, serving as a substrate for enterocytes, protecting the gut barrier func-
tionality, being an energy substrate for lymphocytes and neutrophils, and promoting
production of nucleotides [15]. Several studies have compared enteral feeding supple-
mented with glutamine to the same diet without the added glutamine in burn, trauma,
and ICU patients. Garrel et al. [16] studied 45 severe burn patients and demonstrated
that the addition of 26 g of enteral glutamine substantially decreased infections and
mortality rates. The ASPEN recommendations are based on seven studies that rep-
resent a beneficial effect of adding glutamine. For burn, trauma, and ICU patients,
ASPEN recommends supplementing with 2 3 doses of glutamine a day for a total
of 0.3 0.5 g/kg per day to formulas not containing additional glutamine [2]. ESPEN
recommends supplementing glutamine only to burn and trauma patients [1].
Arginine
Arginine is an amino acid that becomes essential in times of stress. Arginine is
involved in secretion of anabolic hormones, wound healing, support of the immune
system, and detoxification of ammonia. Arginine- enriched formulas have been found
to have a clinical effect of reducing the risk of infections and shortening the duration
of hospitalization of upper gastrointestinal surgical patients [17]. Heyland and Novak
[18] suggest in a meta- analysis that formulas supplemented with arginine have been
found to increase mortality rates in general ICU patients that include sepsis and SIRS
by promoting nitric oxide production that increases tissue damage and could lead to
cardiovascular collapse. The studies of Bertolini et al. [19] support these conclusions.
The review of Marik and Zaloga [20] suggests that the combination of arginine and
fish oil in critically ill patients neutralizes the beneficial effect of fish oil on mortality
rates. Clinical proof suggests providing arginine- enriched formulas to patients before
and after major surgery and trauma and not to provide these formulas to patients suf-
fering from severe sepsis [2].
Omega- 3 Fatty Acids
Omega- 3 fatty acids help downregulate the inflammatory response and improve
overall immune functions. Both eicosapentaenoic acid and docosahexaenoic acid
show benefits in membrane structure and function and gene transcription [20].
Three studies have compared the effects of formulas enriched with fish oil, borage
oil, and antioxidants with similar formulas that do not contain immune- nutritional
components in ventilated patients suffering from acute lung injury or acute respira-
tory distress syndrome. All three studies demonstrated improved clinical outcomes
in the patients who received the formulas enriched with omega- 3 and antioxidants
shorter hospitalization duration and ventilation. Two of the studies showed lower
Enteral Nutrition 55
28- day mortality rates [21 23]. In a meta- analysis looking at the effect of immunonu-
trition components on mortality rates, it was shown that only fish oil demonstrated
significant benefits [20]. In contrast to these studies, a double- blind study by Rice et
al. [24] examined the effect of adding two doses of omega- 3 and antioxidants per day
to standard enteral feeding. The results of this study show that the additional omega-
3 did not provide clinical benefits and may have even worsened the outcomes. The
different results in studies using fish oil- supplemented formula are likely to be related
to changes in the formulation and dosages of the fish oil [14]. However, the current
recommendation is that patients suffering from acute lung injury or acute respiratory
distress syndrome be fed with formulas with a fat profile that provides borage oil and
fish oil enriched with antioxidants [1, 2].
Special Formulas for Specific Clinical Conditions
For patients that are not candidates for immunonutrition formulas, a specialized
formula can be considered that fits the patients condition (i.e. kidney failure and
severe malabsorption). When there is no indication for a specialized formula, it is
recommended to combine standard high- protein formulas or to use protein supple-
mentation in order to reach the recommended levels. The PEP uP protocol, which is
designed to improve enteral energetic and protein consumption, suggests adding 24 g
of protein to the enteral formulas [25]. Formulas that are polypeptide- based are usu-
ally enriched with MCT fatty acids and have higher osmolality. They are to be used in
patients suffering from short bowel syndrome or severe malabsorption.
According to ASPEN [2], patients suffering from prolonged diarrhea, in who use
of hyperosmolar formulas and infection with Clostridium difficile have been ruled
out, should try to use formulas enriched with solvable fibers. Another option is to use
polypeptide- based formulas. It is important to note that since there are no supporting
studies, these recommendations are based on expert opinion.
Probiotics, prebiotics, and synbiotics are also used with ICU patients. Prebiotics is
defined as selectively fermented ingredients (mainly carbohydrates) that allow spe-
cific changes both in the composition and activity in the gastrointestinal microflora
which confer benefits upon the hosts well- being and health. The term synbiotics
refers to products that combine prebiotic and bioactive lactic acid bacteria (probiot-
ics) [26]. A study following patients suffering from acute pancreatitis demonstrated
that feeding an enteral formula with prebiotics (a mixture of fructooligosaccharides
and other soluble and insoluble fibers) significantly improved hospital stay and com-
plication rate [27]. More studies are needed to determine the clinical effect of enteral
formulas supplemented with prebiotics in critically ill patients [14].
With patients suffering from fluid retention, such as pulmonary edema, anuria,
or any other condition that requires fluid restrictions, it is recommended to integrate
concentrated enteral formulas of 1.5 2 kcal/ml. Patients suffering from acute renal
failure will benefit from standard formulas. In situations where there are electrolyte
abnormalities, it is recommended integrating a specialized formula with a unique
56 Anbar
electrolyte profile [28]. Patients suffering from cirrhosis or liver failure could use a
standard formula without protein limits. In case of encephalopathy and in severe situ-
ations, branched- chain amino acid formulation could be used.
In conclusion, in order to optimally adapt the formula given to the ICU patient,
one must look at the patients medical status, nutritional state, nutritional goals, and
functionality of the gastrointestinal tract, and assess the different components and
attributes of the formulas. Choosing a right enteral feeding formula can positively
affect a patients outcome.
Complications
Enteral feeding is known as safe and effective, but the possibilities for complications are
present, which include mechanical, gastrointestinal, and metabolic complications.
Aspiration is the most severe potential complication of enteral feeding and is a
main cause of pneumonia. Some patients have increased risk factors for aspiration
such as ventilated patients, old age, decreased consciousness, supine position, poor
oral health, etc. [2]. In order to reduce the risk of aspiration, it is important to main-
tain a posture where the upper body is raised to 30 45, assess the tolerance for feed-
ing, and assess transition to postpyloric feeding.
Gastrointestinal complications that are linked with enteral feeding include nausea,
vomiting, diarrhea, constipation, abdominal pain, and bloating. The most common
gastrointestinal complication in the ICU is diarrhea, which affects up to 60% [29].
With diarrhea, potential causes need to be verified; soluble fiber- enriched solution
can be used, as well as a polypeptide- based formula for severe cases.
In the ICU patient, development of metabolic complications and their severity are
mainly linked to the medical condition of the patient and can cause electrolytic dis-
turbances. Special attention should be given to the possible development of refeeding
syndrome.
Refeeding Syndrome
The refeeding syndrome is a group of symptoms that appear after sudden feeding of
a patient who was in a starved state. The sudden change effects hormone secretions
that in turn cause changes in electrolytes and fluids [30]. These changes can cause
cardiogenic, respiratory, hematological, metabolic, and neurological disturbances,
as well as multiorgan failure and death in severe cases. The electrolytic disturbances
include risks of hypophosphatemia, hypokalemia, and hypomagnesemia. In addition,
there have been reported cases of disturbance to the metabolism of glucose and defi-
ciencies in trace elements, vitamins, and especially thiamine. The starved patient has
a metabolic profile that exposes him to risks such as refeeding syndrome and reduced
Enteral Nutrition 57
1 Kreymann KG, Berger MM, Deutz NEP: ESPEN
guidelines on enteral nutrition: intensive care. Clin
Nutr 2006;25:210223.
2 McClave SA, Martindale RG, Vanek VW, 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 for Parenteral and Enteral
Nutrition. JPEN J Parenter Enteral Nutr 2009;33:
277 316.
3 Heyland DK, Dhaliwal R, Drover JW: Canadian
clinical practice guidelines for nutrition support in
mechanically ventilated, critically ill adult patients.
JPEN J Parenter Enteral Nutr 2003;27:355373.
4 Marik PE, Zaloga GP: Early enteral nutrition in
acutely ill patients: a systematic review. Crit Care
Med 2001;29:2264 2270.
5 Doig GS, Heighes PT, Simpson F: Early enteral
nutrition, provided within 24 h of injury or inten-
sive care unit admission, significantly reduces mor-
tality in critically ill patients: a meta- analysis of
randomized controlled trials. Intensive Care Med
2009;35:2018 2027.
6 Singer P, Berger MM, Van den Berghe G: ESPEN
guidelines on parenteral nutrition: intensive care.
Clin Nutr 2009;28:387 400.
7 Weijs PJ, Stapel SN, de Groot SD, et al: Patients: a
prospective observational cohort study optimal
protein and energy nutrition decreases mortality in
mechanically ventilated, critically ill. JPEN J
Parenter Enteral Nutr 2012;36:60 68.
8 Dickerson RN: Hypocaloric feeding of obese
patients in the intensive care unit. Curr Opin Clin
Nutr Metab Care 2005;8:189196.
ATP stores, vitamins, and electrolytes. When feeding is restarted, four main changes
occur: increase in insulin secretion, inhibition of glucagon production, activation of
anabolic processes, and transition from lipolysis to lipogenesis [31].
In the ICU, it is critical to identify patients with a high risk of refeeding syndrome.
These include patients suffering from severe malnutrition, anorexia nervosa, HIV,
alcoholism, and cancer. Multidisciplinary teams of doctors, nurses, and dietitians can
assist in the identification and elimination of complications [31]. It was found that in
the ICU, the rate of patients who develop refeeding syndrome expressed as hypophos-
phatemia was 34% [32].
When an ICU patient is diagnosed as being at high risk of developing refeed-
ing syndrome, the electrolyte profile should be determined before starting feeding.
It is recommended to start feeding slowly and gradually. In ICU patients, it is rec-
ommended to start with 20 75% of the energy need, according to the severity of
nutritional depletion, and also to consider the energy that is obtained through non-
nutritional sources such as propofol and intravenous glucose [31]. Nutritional goals
can be achieved in 3 7 days. There are no standard recommendations about addi-
tional thiamine and minerals.
Implementation of enteral feeding is a central and challenging aspect of the nutri-
tional support in the critically ill patient. Setting of nutritional goals, early feeding,
route of administration, selecting an appropriate formula, and identifying patients
with higher risk for developing complications form the optimal nutritional treatment
and contribute to improved patient outcome.
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Ronit Anbar, RD
Institute for Nutrition Research and Nutrition Unit
Rabin Medical Center, Beilinson Hospital
IL 49100 Petah Tikva (Israel)
E- Mail roniti@clalit.org.il
Requirements, Routes of Administration and Prescription
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 5968
Parenteral Nutrition
Ronan Thibault
a c
Claude Pichard
d
a
Clermont Universit, Universit dAuvergne, Unit de Nutrition Humaine,
b
INRA, UMR 1019, UNH,
CRNH Auvergne, and
c
CHU Clermont- Ferrand, Service de Nutrition Clinique, Clermond- Ferrand, France;
d
Nutrition Unit, Geneva University Hospital, Geneva, Switzerland
Abstract
Parenteral nutrition (PN) is a technique of nutritional support, which consists of intravenous admin-
istration of macronutrients (glucose, amino acids, and triglycerides), micronutrients (vitamins and
trace elements), water, and electrolytes. Early studies indicate that the use of total PN was associated
with increased mortality and infectious morbidity. These detrimental effects of PN were related to
hyperglycemia and overfeeding at a period when PN was administered according to the principle
that the higher calories the patients received, the better their outcome would be. Enteral nutrition
(EN) then replaced PN as the gold standard of nutritional care in the intensive care unit (ICU).
However, EN alone is frequently associated with insufficient energy coverage, and subsequent
protein- energy deficit is correlated with a worse clinical outcome. Infectious and metabolic compli-
cations of PN could be prevented if PN is used by a trained team using a validated protocol, only
when indicated, not within the first 2 days following ICU admission, and limited through the time. In
addition, energy delivery has to be matched to the energy target, and adapted glucose control
should be obtained. In patients with significant energy deficit (>40%), the combination of PN and
EN, i.e. supplemental PN, from day 4 of the ICU stay, could improve the clinical outcome of ICU
patients as compared with EN alone. Therefore, PN should be integrated in the management of ICU
patients with the aim of prevent the worsening of energy deficits, allowing the preservation of lean
body mass loss, and reducing the risk of undernutrition- related complications.
Copyright 2013 S. Karger AG, Basel
Critical illness is accompanied by increased protein catabolism and a negative nitrogen
balance [1] (fig. 1). Increased catabolism is mainly observed in the skeletal muscles,
leading to fat- free mass loss, alteration in muscular function, and delay of mechanical
ventilation weaning. Therefore, to limit the clinical impact of the increased catabo-
lism, nutritional support is integrated into the management of the intensive care unit
(ICU) patients. Parenteral nutrition (PN) consists of the intravenous administration
of macronutrients (glucose, amino acids, and triglycerides), micronutrients (vita-
mins and trace elements), and electrolytes. The clinical practices regarding the use of
PN have evolved through time [2]. At present, there is a need to reconsider PN as a
60 Thibault Pichard
nutritional support aiming at optimizing the protein- energy balance and preserving
the loss of fat- free mass during the first week following ICU admission.
Evolution of the Use of Nutrition Support through Time
In the 1970s, the systematic use of PN was the first choice of nutrition support in
ICUs. Glucose, lipids, and amino acids were administered separately and with incon-
sistent flow rates, with the idea that the higher calories the patients received, the
better the outcome. This early use of total PN (TPN) results in the excess administra-
tion of calories, particularly from carbohydrates and fats, named overfeeding. The
link between TPN- induced overfeeding, hyperglycemia, infectious complications,
Critical illness
Systemic infammation
SIRS
Overfeeding Insulin resistance
Hyperglycemia
+
Neoglucogenesis
- Optimized PN
- SPN
Adapted
glucose control
Negative impact on clinical outcome:
Infections
Liver steatosis and dysfunction
Mortality
Hypercatabolism:
Proteolysis
Lipolysis
Fig. 1. Physiopathology and consequences of hyperglycemia during critical illness. Critical illness is
responsible for a systemic inflammation resulting from the systemic inflammatory response syn-
drome (SIRS). Systemic inflammation induces metabolic disorders characterized by: (1) hypercatabo-
lism of fat- free mass and fat mass, leading to increased muscle proteolysis and increased adipose
tissue lipolysis, the goal of which is the production of glucose, through neoglucogenesis, to cover
brain glucose needs; and (2) peripheral insulin resistance, mainly in skeletal muscles and liver. These
two metabolic disorders lead to hyperglycemia, which negatively affects clinical outcome by increas-
ing the risks of infections, liver steatosis and dysfunction, and mortality. Therefore, preventing over-
feeding by an optimized PN or the combination of EN with PN, namely SPN is associated with an
adapted glucose control and, in turn, a better clinical outcome.
Parenteral Nutrition 61
impaired immunity, and mortality was clearly established in the 1980s [3 5] (fig. 1)
at the moment when the progress of intensive medicine allowed saving severe ICU
patients from early death. Thus, enteral nutrition (EN) progressively replaced TPN
as the gold standard nutritional therapy. Thanks to its beneficial effects on clinical
outcome [6, 7], current guidelines now recommend early EN as the first indicated
feeding route in ICU patients [8 11]. However, EN alone is often unable to fully cover
the nutritional needs [12 16], leading to a cumulated protein- energy deficit during
the first week of ICU stay, which is associated with a worse clinical outcome [15, 16].
Necessity for Reconsidering Parenteral Nutrition as a Nutrition Support in Intensive
Care Unit Patients
Parenteral Nutrition Is Not as Detrimental as Previously Reported
The industrial PN solutions have evolved considerably during the last two decades,
and all- in- one solutions are now widely implemented in the ICU. They allow obtain-
ing a lower and constant load of glucose and lipids, reducing the risk of hyperglyce-
mia, hypertriglyceridemia, and liver fat overload. This risk has also been reduced by
the increased use of the mix of long- and medium- chain triglycerides and of olive oil-
enriched lipid emulsions. Therefore, studies performed before 1990 no longer reflect
the current clinical practice. As a result, meta- analyses have indicated that PN is not
associated with increased morbidity and mortality [17, 18]. Also, adequate glucose
control, aiming at maintaining glycemia below 10 mmol/l and avoiding hypoglyce-
mia, by appropriate nutritional support along with insulin administration, reduces
ICU mortality and morbidity [19, 20] (fig. 1).
The Medical Environment and Patients Are Changing
The improvement of medical technology (e.g. better mechanical ventilation, infec-
tion control, and hemodynamic management) is associated with better patient sur-
vival. As a result, undernutrition has a greater clinical impact on infection rates,
prolonged length of stay, and delayed recovery. In addition, as more patients admit-
ted in the ICU are elderly, obese, and have increased prevalence of chronic diseases
(cancer, degenerative neurological diseases, organ insufficiency), more patients with
pre- existing undernutrition and/or lean tissue depletion (e.g. sarcopenic obesity)
are being seen. As these conditions are incompatible with stress- induced catabo-
lism and rapid healing and recovery, the prevention of their onset or worsening is
warranted.
Limiting the Energy Debt during the First Week Improves Clinical Outcome
In 2009, the European and American Societies for Clinical Nutrition and Metabolism
(ESPEN and ASPEN) recommended the use of supplemental PN (SPN), i.e. the com-
bination of PN with EN, for patients not receiving sufficient protein- energy intake
62 Thibault Pichard
by EN alone within 24 48 h and after the 7th day following ICU admission [10, 11],
respectively (table 1). Two prospective randomized controlled clinical trials brought
new light on the use of SPN in ICU patients [22, 23]. The EPaNIC study [22] showed
that the systematic use of SPN beginning 48 h following ICU admission was associ-
ated with an increased rate of infections and a lengthened ICU stay and duration of
mechanical ventilation, as compared with PN initiated after day 7. In the Swiss SPN
study (published in an abstract form [23]), SPN delivered after day 4 following admis-
sion to cover 100% of the energy target in ICU patients not covering 60% of their
energy needs by day 3 reduced the rate of new infections and antibiotherapy duration
in comparison with EN alone. The methodological differences between these two tri-
als are shown in table 2. The EPaNIC trial confirms that there is an increased risk of
infections related to overfeeding [3 5] in the acute phase of critical illness, i.e. within
72 h following ICU admission [16]. This could be related to the increased hepatic
production of energy at this acute phase, leading to the reduction of glucose and lipid
utilization. In the subgroup of selected patients in whom well- conducted EN failed,
the prevention of the worsening of energy deficit by SPN improves the clinical out-
come [15], and should allow preventing fat- free mass loss and promote better chances
of recovery and quality of life after the ICU stay.
Table 1. Guidelines for the use of PN and the combination EN- PN in ICU patients (adapted from [21])
ESPEN [8, 11] ASPEN [10] Canadian [9]
1. PN should be avoided in
patients who tolerate EN and
are covering
their energy target (A)
1. Nutrition support therapy in the form of
EN should be initiated in critically ill
patients who are unable to maintain
volitional intake (C)
1. For critically ill patients starting on
EN, we recommend that PN not be
started at the same time as EN (B)
2. PN has to be initiated 2448 h
following ICU admission in all
patients unable to cover their
nutritional needs by oral
intake in the 3 days following
their admission if EN is
contraindicated or not
tolerated (C)
2. If early EN is not feasible or available
during the first 7 days following admission
to the ICU, no nutritional support therapy
should be provided in non-
undernourished patients (C); in previously
undernourished patients, PN should be
initiated as soon as possible following
admission and adequate resuscitation (C)
2. and 3. For patients not tolerating
adequate EN, there are insufficient
data to put forward a
recommendation about when PN
should be initiated (B)
3. SPN is indicated for all
patients receiving EN who do
not reach their target energy
needs after 48 h (C)
3. Initiating SPN before this 7- to 10- day
period in the patient already on EN does
not improve outcome and may be
detrimental to the patient (C)
The level of recommendations according to the evidence- based medicine classification is indicated between parentheses.
Levels of recommendations: A = meta- analysis of randomized controlled trials, or at least 1 randomized controlled trial; B =
controlled, nonrandomized trials, or well- designed descriptive studies; C = expert opinions.
Parenteral Nutrition 63
Indications for Parenteral Nutrition in Intensive Care Unit Patients
PN is only indicated in patients contraindicated for EN, e.g. in case of intestinal occlu-
sion which is the only absolute contraindication to EN. In all other cases, PN should
only be used in patients who are not expected to be on normal nutrition within 3
days when EN is not feasible, unsuccessful, or insufficient. PN complications, such
as hyperglycemia and infections, can be avoided if PN is used: (1) by a trained team
using a validated protocol [3, 4], (2) only when indicated, (3) not within the first 2
days following ICU admission, (4) limited through the time, (5) with energy delivery
matched to target, (6) together with an adapted glucose control, and (7) in association
with oral nutrition or EN.
Parenteral Nutrition: Administration and Formulas
Route of Access
The majority of PN solutions are hyperosmolar and deliver through a central venous
catheter (CVC). The use of a single lumen polyurethane or silicone catheter is prefer-
able, unless one port of a multilumen catheter is exclusively assigned to PN admin-
istration. The preferred site for CVC insertion is the subclavian vein. Subcutaneous
tunneling is recommended to reduce the risk of catheter infections. PN may be given
by peripherally inserted CVC (PICC line), midline fine- bore catheters (for PN
Table 2. Main methodological differences between the EPaNIC [23] and SPN [22] studies
Parameters EPaNIC SPN
Number of included patients 4,640 305
Centers 2 (7 units) 2 (2 units)
Energy deficit as an inclusion criterion no yes
Exclusion if BMI <17 yes no
Admission in emergency, % 42 83
Cardiac surgery, % 61 13
ICU length of stay, % <3 days: 50.0
<4 days: 40.5
7 days: 29.8

9 days: 96
Energy target assessment 25 kcal/kg ideal BW/day indirect calorimetry at day 3
EN progression slow fast
64 Thibault Pichard
expected to exceed 6 days), and peripherally by standard short catheters. Teflon or
polyurethane catheters should be chosen, placed in an upper extremity site prefer-
ably, and changed daily or every 48 72 h to minimize the risk of phlebitis.
Peripheral PN could be used when PN through a CVC is postponed. Peripheral
PN can be used as a supplemental therapy to optimize the nutritional coverage of
patients at high risk of developing malnutrition or being malnourished with insuf-
ficient EN. Peripheral PN should not exceed 10 days since its composition gener-
ally does not allow covering the nutritional needs. However, evidence- based data are
scarce for supporting the use of peripheral PN in ICU patients. Well- designed pro-
spective studies should address this issue.
Energy and Nutrients
To prevent overfeeding- related complications, ESPEN recommends not delivering
more than 20 25 kcal/kg actual body weight (BW)/day of energy during the acute
phase of critical illness [8, 11]. During the postacute phase, energy delivery should
be 25 30 kcal/kg actual BW/day [8, 11]. In obese or overweight patients, the energy
requirements can be estimated as 15 kcal/kg actual BW/day or 20 kcal/kg ideal
BW/day, and protein needs can be estimated as between 1.2 and 1.5 g/kg adjusted
BW/day [8, 11, 24].
Nitrogen sources are provided by a balanced mixture of amino acids. There are
no convincing arguments to recommend the use of branched- chain amino acids. To
avoid the risks of PN- related metabolic and infectious complications, glucose deliv-
ery should not exceed 6 g/kg/day, at rates below 5 mg/kg/min, and lipid supply must
not exceed 23 mg/kg/min or 60% of total energy input. In addition, PN should be
continuously administered for 24 h. However, there is no consensus regarding the
ideal quantity of lipids. An initial supply of 0.5 1 g/kg/day of long- chain triglycerides
seems to be best; this can be increased up to a maximum of 2 g/kg/day if triglyc-
eridemia and serum lactescence are regularly monitored. The immunosuppressive
effect of standard lipid emulsions remains controversial. Within the context of severe
trauma/sepsis, lipid supply is limited to about 30 40% of nonprotein calorie input.
All- in- One Parenteral Nutrition Solution
All- in- one (ternary) PN bags, containing protein, carbohydrates, and lipids, or
binary bags containing carbohydrates and protein, supplemented with trace ele-
ments, vitamins, and electrolytes, are generally recommended for their convenience
and good metabolic tolerance. Binary bags allow modification of lipid administra-
tion. Convenient and simplified administration protocols are possible, and in par-
ticular, initiation/interruption of PN infusion is permissible.
Pharmaconutrition
Glutamine added to the PN solution improves the clinical outcome of abdominal sur-
gery and trauma ICU patients [25]. A grade A recommendation is stated by ESPEN
Parenteral Nutrition 65
in those patients [11]. However, the optimal dosage and timing of administration of
glutamine is not known. Arginine should not be used in patients with severe sepsis
(APACHE II >15) since it has been associated with increased mortality. The admin-
istration of omega- 3 polyunsaturated fatty acids together with PN in ICU patients
could reduce the ICU length of stay [26]. The presumed clinical benefits of the asso-
ciation of PN with omega- 3 polyunsaturated fatty acids in patients with acute lung
injury were recently contested by a randomized trial showing an increased rate of
nosocomial infections in ICU patients receiving enteral omega- 3 polyunsaturated
fatty acids [27]. In ICU patients with burns, the supplementation with antioxidant
trace elements, such as zinc, selenium, and copper, is highly beneficial as it reduces
morbidity, mortality, and length of stay [28].
Complications of Parenteral Nutrition: Description and Management
Although the PN technique has evolved considerably over the last two decades, PN
should be used cautiously to avoid complications.
Catheter- Related Sepsis
The risk of catheter infections is the major complication of PN in ICU patients.
The PN indication should be re- evaluated daily, and PN should not be lengthened
unnecessarily.
To reduce the risk, subclavian vein access and subcutaneous tunneling are rec-
ommended. Subcutaneous tunneling is warranted for internal jugular and femoral
catheters. All the manipulations of the CVC (insertion, nursing care, and con-
nection of PN solution) require strict adherence to antiseptic protocols. The tub-
ing connecting the PN bag to the catheter should be changed daily. Routine CVC
replacement (new site or guide- wire exchange) is not recommended because it
increases the risks of mechanical complications and device- related infection. The
prevention of catheter- related sepsis includes the prevention of overfeeding and
hyperglycemia.
Rigorous infection control is mandatory in patients receiving PN. Body temper-
ature and catheter insertion sites (including peripheral) must be carefully moni-
tored. A low- grade fever or an inflamed or purulent insertion site may be a sign of
catheter infection. If catheter- related sepsis is suspected to be the cause of severe
sepsis or septic shock, the catheter must be removed immediately, PN temporar-
ily interrupted, blood and catheter cultures obtained, and intravenous antibiotic
treatment initiated. In the case of mild infection, unjustified CVC removal and the
risks associated with the placement of a new catheter in a new site must be avoided;
options which have been discussed are: guide- wire exchange for quantitative cul-
ture of the catheter tip, taking cultures in situ, and in situ antibiotic treatment (anti-
biotic clamp).
66 Thibault Pichard
Other Catheter- Related Complications
Complications associated with catheter insertion, such as air embolism, injury to tho-
racic structures (lung, pleura, arteries, etc.), and cardiac arrhythmias, are not uncom-
mon. General safety guidelines, not specific to PN, should be strictly applied. Catheter
thrombosis can occur any time after the insertion and is often associated with cath-
eter infection. Heparinization of PN bags or solutions is sometimes advocated.
Metabolic Complications
Hyperglycemia is frequently observed in the ICU, especially in patients with infection,
liver dysfunction, pancreatic dysfunction, diabetes mellitus, and those receiving drugs
such as corticosteroids and cephalosporins. Blood and urine glucose values should be
checked daily, and up to several times per hour in patients treated with insulin.
Hypoglycemia is much less common, and may be caused by the sudden cessation
of a hypertonic glucose infusion, a too- tight glycemic control, or the onset of the sep-
sis syndrome.
Hyperlipidemia may be attributed to excessive administration, overproduction, or
underutilization of fat. Lipid overproduction can be the result of excessive delivery of
carbohydrates, and can result in hepatic steatosis. Triglyceridemia should be moni-
tored at least twice a week in ICU patients receiving PN.
Liver Enzymes Abnormalities
More than 60% of ICU patients receiving PN for more than 2 weeks may show mul-
tifactorial abnormal liver function tests. These abnormalities are usually benign, but
may herald the onset of multiple organ failure. Liver enzyme abnormalities are usu-
ally multifactorial: sepsis, hypoxemia, ischemia, drugs, and PN [29]. An increase in
- glutamyl transpeptidase and alkaline phosphatases without an increase in bilirubin
is frequent during PN administration. The differential diagnosis of ICU jaundice is
often difficult due to these numerous possible etiologies. Aspartate aminotransferase,
alanine aminotransferase, - glutamyl transpeptidase and alkaline phosphatases, and
bilirubin should be checked twice a week.
Sludge in the biliary tract and stasis in the biliary ducts causing chronic acalcu-
lous cholecystitis may be associated with prolonged PN and can be prevented by the
administration of a small volume of EN (100200 ml/day). Gangrenous cholecystitis
is a rare but often severe, life- threatening complication of TPN in mechanically venti-
lated patients with liver dysfunction.
Refeeding Syndrome
Patients with severe undernutrition (body weight loss 20%) are at high risk of refeed-
ing syndrome. When nutritional support is started in an undernourished patient, the
intracellular demands for phosphate and potassium are increased due to enhanced
glycolysis and Na/K- ATPase pump stimulation. In practice, phosphate and potas-
sium delivery should increase from 15 30 to 30 60 mmol PO
4
/day and from 80 120
Parenteral Nutrition 67
1 Hill GL: Jonathan E. Rhoads Lecture. Body compo-
sition research: implications for the practice of clini-
cal nutrition. JPEN J Parenter Enter Nutr 1992;16:
197 218.
2 Berger MM, Chiolro RL, Pannatier A, Cayeux
MC, Tappy L: A 10- year survey of nutritional sup-
port in a surgical ICU: 1986 1995. Nutrition 1997;
13:870 877.
3 Jeejeebhoy KN: Total parenteral nutrition: potion or
poison? Am J Clin Nutr 2001;74:160 163.
4 Ziegler TR: Parenteral nutrition in the critically ill
patient. N Engl J Med 2009;361:1088 1097.
5 Marik PE, Pinsky M: Death by parenteral nutrition.
Intensive Care Med 2003;29:867869.
6 Artinian V, Krayem H, DiGiovine B: Effects of early
enteral feeding on the outcome of critically ill
mechanically ventilated medical patients. Chest 2006;
129:960 967.
7 Peter JV, Moran JL, Phillips- Hughes J: A metaanaly-
sis of treatment outcomes of early enteral versus
early parenteral nutrition in hospitalized patients.
Crit Care Med 2005;33:213.
8 Kreymann KG, Berger MM, Deutz NE, et al: ESPEN
guidelines on enteral nutrition: intensive care. Clin
Nutr 2006;25:210223.
9 Heyland DK, Dhaliwal R, Drover JW, et al; Canadian
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;27:355373.
10 Martindale R, McClave S, Vanek V, et al: Guidelines
for the provision and assessment of nutrition sup-
port therapy in the adult critically ill patient: Society
of Critical Care Medicine and American Society for
Parenteral and Enteral Nutrition: executive sum-
mary. Crit Care Med 2009;37:1757 1761.
to 120 200 mmol KCl/day. The electrolyte deficit could lead to heart insufficiency,
severe neurological disorders, and death. The prevention of refeeding syndrome is
mandatory. A systematic and daily measurement of plasma phosphate, potassium,
calcium, and magnesium is indicated in the most severely undernourished ICU
patients. Prevention of lactic acidosis, beriberi, and/or Wernickes encephalopathy is
achieved by high vitamin B
1
levels before hypertonic glucose is started. Reversal of
acidemia following the establishment of mechanical ventilation may result in hypo-
phosphatemia due to a shift of phosphate from the extracellular to the intracellular
compartments.
Conclusion
PN is associated with infectious and metabolic complications. Therefore, PN should
be restricted to the EN contraindications or failure of EN to achieve nutritional needs.
If PN indications and recommendations are respected, and overfeeding avoided, PN
is a safe therapy for ICU patients. Typical ICU patients are old and have chronic dis-
eases, a pattern that increases vulnerability towards stress- related catabolism. The
optimization of the nutritional therapy by PN, when EN is insufficient, could prevent
the worsening of negative energy balance, thus reduce the onset of infections. The
objectives of the nutritional therapy is the reduction of undernutrition- related mor-
bidity, mortality, and global health care costs, and the preservation of lean body mass
allowing the rapid restoration of body functions after the ICU stay.
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Claude Pichard, MD, PhD
Unit de Nutrition Hpitaux Universitaires de Genve
Rue Gabrielle- Perret- Gentil, 4
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How Can Nutrition Interfere with Outcome?
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 6981
Can Nutrition Support Interfere with
Recovery from Acute Critical Illness?
Rifka C. Schulman Jeffrey I. Mechanick
Division of Endocrinology, Diabetes, and Bone Diseases, Mount Sinai School of Medicine, New York, N.Y., USA
Abstract
Malnutrition, following critical illness- related metabolic and immune neuroendocrine derange-
ments, is exacerbated by energy and protein deficits beginning early in the intensive care unit (ICU)
stay. While nutrition support is an important component of ICU care, adverse effects can occur.
Underfeeding, due to insufficient energy and/or protein is associated with poor patient outcomes.
Overfeeding carbohydrates, lipids, and/or protein can result in hyperglycemia, hypertriglyceridemia,
hepatic dysfunction, and/or azotemia. Individualization of the nutritional prescription with clinical
monitoring and repeated adjustment is necessary to avoid harm. Appropriate use of tight glycemic
control protocols in combination with nutrition support can prevent hyperglycemia, while minimiz-
ing glycemic variability and hypoglycemic events. While the enteral route is favored for nutrition
support, early supplemental parenteral nutrition should be considered in selected high- risk patients.
Thus, risk stratification of patients upon admission to the ICU can be helpful to design individualized
nutritional prescriptions maximizing benefit while avoiding potential interference with recovery.
Copyright 2013 S. Karger AG, Basel
Critical illness is characterized by severe cytokine- mediated inflammation and
catabolism, irrespective of the specific inciting disease. Stress- related organ dysfunc-
tion is compounded by polypharmacy, immobilization, technological interventions,
and other iatrogenic factors. Indeed, hypermetabolism and hypercatabolism with
increased resting energy expenditure and nitrogen losses, respectively, are consis-
tently observed. Severe protein- calorie malnutrition is also common in the intensive
care unit (ICU), and is associated with increased infectious rates, impaired wound
healing, prolonged length of stay, and increased mortality [1]. Thus, nutrition sup-
port, the provision of enteral nutrition (EN) or parenteral nutrition (PN) to patients
unable to tolerate adequate oral nutrition, serves as a seemingly appropriate remedy
to improve organ function, preserve lean body mass, and attenuate oxidative tissue
damage [2].
70 Schulman Mechanick
In contrast to an aggressive cardiopulmonary and ventilator management
focus, nutrition support has been generally deprioritized in critical care medicine.
Fortunately, this treatment paradigm has evolved where nutrition support has
gained greater attention in recent years. However, with greater attention comes a
greater awareness of problems and obstacles. While nutrition support may confer
net benefit in certain patients if managed correctly, it intrinsically has the poten-
tial for harm. For instance, both under- and overfeeding, commonplace in the
ICU, are associated with complications. Additionally, physical placement of access
devices can cause complications and hinder recovery. Therefore, at first glance,
suboptimal nutrition support can hamper optimal recovery from acute critical ill-
ness (ACI). However, with further thought, a more significant question emerges:
Does optimal nutrition support adversely affect the recovery from ACI? In other
words, if nutrition support is provided with extensive diligence, consistent with
the extant evidence, will it always provide a net benefit to the acute critically ill
patient?
Metabolic Model of Critical Illness
While homeostasis is the ability of an organism to maintain essential parameters
(e.g. pH, blood pressure, pulse) within a narrow range, allostasis governs adjustment
of homeostatic set- points in response to a changing environment [3]. Allostatic adap-
tation (or allostatic load) preserves the integrity of an organism in the stressed state,
but with time, allostatic overload occurs. This process can be regarded as an excessive
cost of adaptation, such as when too much muscle protein is catabolized or too much
calcium is liberated from bone. Using the framework of allostasis and centering on
activation of the immune- neuroendocrine axis, critical illness is conceived of as four
distinct stages: (1) ACI, (2) prolonged acute critical illness (PACI), (3) chronic critical
illness (CCI), and (4) recovery from critical illness [4].
ACI follows a physiological insult, triggering a cascade of immune- neuroendocrine
axis and metabolic responses, conferred by natural selection to promote survival of
the organism. This fight or flight reaction or stress response drives a network of
immune and neuroendocrine signals that divert metabolic pathways towards catabo-
lism. This provides crucial substrates for wound healing and enhanced organ func-
tion necessary for organismal survival. Inflammatory cytokines stimulate skeletal
muscle proteolysis to liberate free amino acids, downregulate reverse phase protein
(e.g. albumin) synthesis, and upregulate acute phase protein (e.g. globulin) synthe-
sis. This, in turn, leads to progressive lean body mass loss and a kwashiorkor- like
malnutrition picture, both to be viewed more as allostatic markers rather than patho-
logical instigators [5, 6]. Furthermore, an increase in gluconeogenesis coupled with
decreased peripheral glucose uptake engenders a state of insulin resistance and stress
hyperglycemia [7].
Nutrition Support and ACI 71
PACI refers to a state of persistent inflammation, catabolism, and insulin resis-
tance, beginning at about day 3 of critical illness [7, 8]. Unlike ACI, this stage is
characterized by blunted immune- neuroendocrine axis throughput, although hyper-
cortisolism can persist independently [9]. From a systems standpoint, the complexity
and chaotic rhythms among biological oscillators, characteristic of a healthy biologic
state, are dampened as physiomic networks become uncoupled during a protracted
pathological state [10]. Hence, the metabolic derivatives of PACI, no longer predeter-
mined by Darwinian parameters, become detrimental and contribute to the accrual
of allostatic load. Perhaps another perspective would be to view iatrogenesis, in the
form of technology, as an unnatural incursion that corrupts a system designed to pro-
tect and facilitate survival. One can now envision a rough draft of the contention that
nutrition support may subvert, more than nurture, the physiology of critical illness.
CCI is a distinct syndrome comprised of prolonged mechanical ventilation,
kwashiorkor- like malnutrition with sarcopenia, hypoalbuminemia and anasarca,
stress hyperglycemia, impaired neuroendocrine function, poor wound healing, atten-
uated immune function, hyperresorptive metabolic bone disease, vitamin D defi-
ciency, cognitive dysfunction, and profound debilitation [4]. CCI patients are those
who neither recover nor expire in the first 1 2 weeks of critical illness and enter a
state of allostatic overload. For practical purposes, the onset of CCI is defined by the
placement of a tracheostomy. CCI carries a poor prognosis with generally fewer than
50% of patients liberated from the ventilator, high mortality rates, and a very small
chance of a meaningful recovery [11].
Recovery from critical illness begins with liberation from mechanical ventilation.
At this point, weeks or months of malnutrition may have been so severe that a full
recovery with acceptable quality of life is highly improbable. The most effective man-
agement strategy for this patient population is prevention, with optimal delivery of
nutrition support beginning in ACI to avoid PACI and CCI. Therefore, the question
can be refined. Based on available information and experience, what is the optimal
manner to provide nutrition support during ACI in order to enhance the response
to primary therapies, avoid iatrogenic detriment to natural adaptive mechanisms,
reduce allostatic load, and ultimately prevent PACI, CCI, and death?
Adverse Effects of Nutrition in Acute Critical Illness
Underfeeding is commonplace in the ICU, with reported energy intakes at 49 70% of
calculated requirements [12]. Underprescription of nutrition support is a significant
predicting factor for underfeeding [13]. The amount of EN received by patients is
further reduced by gastrointestinal dysfunction, secondary to acute illness or medica-
tions, and frequent interruptions for procedures. Underfeeding has been associated
with infectious complications, prolonged mechanical ventilation and ICU length of
stay, and increased mortality [12]. Accumulation of an energy deficit as early as the
72 Schulman Mechanick
first week in the ICU has been linked to poor outcomes in observational studies [14].
Underfeeding with resultant malnutrition frequently goes unnoticed in the ICU due
to the lack of easily measurable parameters and the ability of edema to mask loss of
lean body weight [15]. A minimum intake of about 100 g of carbohydrates per day is
recommended to avoid starvation- related catabolism [16].
Importantly, underfeeding of energy and protein are distinct entities, with prescrip-
tion of adequate amounts of each necessary to maximize outcome. Recently, Weijs et
al. [17] performed a prospective observational study with energy targets determined
by indirect calorimetry and a protein goal of 1.2 1.5 g/kg/day. While patients reach-
ing the energy target alone did not show a significant improvement in outcome, the
group meeting both energy and protein targets showed a significant 50% reduction
in 28- day hospital mortality compared to patients reaching neither target. Further,
energy intake and nitrogen balance show a positive correlation, with adequate energy
intake necessary to attenuate hypercatabolism [18].
Attempts in the past at overzealously correcting nutritional deficits have shown
the detriments that can arise from overfeeding, the delivery of nutrition beyond that
of estimated requirements. While overfeeding is more frequently encountered with
use of PN, consequences can be linked to excessive amounts of individual macronu-
trients rather than the mode of delivery.
Overfeeding of dextrose exacerbates a metabolic environment already prone to
stress hyperglycemia and insulin resistance. The significant harmful effects of sus-
tained hyperglycemia have been described, including glycosuria and dehydration,
proinflammatory effects, generation of reactive oxygen species with subsequent tis-
sue damage, induction of pancreatic - cell apoptosis, endothelial cell injury, and
impaired wound healing [7]. Hyperglycemia has been linked to impaired cellular and
humoral immune responses with an increased risk of infectious complications. Close
monitoring of blood sugars during nutrition support, coupled with intensive insulin
therapy (IIT), has been shown to reduce morbidity and mortality in the ICU [19].
Other potential consequences of carbohydrate excess have been described.
Increased generation of CO
2
during carbohydrate oxidation can promote hypercapnia,
respiratory acidosis, and impaired liberation from the ventilator. Hyperinsulinemia,
secondary to large carbohydrate loads, may exacerbate fluid overload due to insulins
direct antinatriuretic effect [20]. Excess dextrose is converted to fatty acids, increas-
ing levels of triglyceride- rich very- low- density lipoproteins, leading to hypertriglyc-
eridemia. Overfeeding of calories and an increased carbohydrate:lipid ratio promote
fat accumulation in the liver, resulting in hepatic steatosis [21]. Monitoring of liver
function tests and triglyceride levels are advised, with reduction in calories from dex-
trose if abnormalities develop.
While sufficient lipid intake (>1 g/kg/week) is critical to prevent essential fatty acid
deficiency [22], overfeeding of intravenous lipids, in PN or as propofol, can be associ-
ated with detrimental effects. Hypertriglyceridemia, developing when the capacity of
lipoprotein lipase to clear triglycerides is exceeded, may interfere with pulmonary gas
Nutrition Support and ACI 73
exchange or predispose to pancreatitis. Parenteral lipids demonstrate immunosup-
pressive properties in vitro and may encourage bacterial and fungal growth in the
setting of poor aseptic precautions [23]. Lipid excess can also induce cholestasis. An
extreme complication is the fat- overload syndrome, characterized by systemic depo-
sition of fat, with acute onset of respiratory distress, hepatopathy, and coagulopathy
[24]. Limiting lipid infusion rates to a maximum of 1 g/kg/day, and reserving lipid-
based PN for dedicated central lines, in the absence of sepsis or fungemia is appropri-
ate. The use of lipid- free PN in ACI, especially when dedicated central lines are not
available, may be considered to avoid potential harm.
Excessive intake of protein stimulates hepatic deamination, generating ammonia,
urea, and predisposing to azotemia when the renal threshold for urea clearance is
surpassed. Azotemia increases obligate renal free water losses, predisposing to hyper-
tonic dehydration and hypernatremia. Increasing the amount of protein in a nutrition
regimen should be accompanied by additional free water and monitoring of BUN,
ammonia, and sodium levels.
Pitfalls common to both under- and overfeeding hamper the ability of clinicians to
accurately prescribe a nutrition support regimen. Body weight measurement is often
unreliable given the fluctuations in fluid status of the typical ICU patient. Obesity
raises unique challenges to the determination of optimal energy and protein targets,
with the need to differentiate fat mass from fat- free mass, the latter being the primary
determinant of resting energy expenditure. Use of weight- based predictive equations
often overestimates requirements in the geriatric population, due to the presence of
sarcopenia with resultant lower resting energy expenditure. Indirect calorimetry, the
gold standard for calculation of energy requirements, requires technical expertise to
operate and is often unavailable at many institutions. Nitrogen losses via diarrhea,
vomiting, wound or ostomy drainage, and hemodialysis complicate the determina-
tion of protein requirements. Hypoalbuminemia correlates with the degree of inflam-
mation and may not reflect adequacy of the nutrition regimen.
Refeeding syndrome is a serious potential complication that may develop when
nutrition support is initiated in the chronically or severely malnourished patient.
Hypophosphatemia, hypokalemia, hypomagnesemia, thiamine deficiency, fluid over-
load, and/or multiorgan dysfunction may result following the reintroduction of a car-
bohydrate load to the starved patient, related to an insulin surge and depletion of
phosphorylated intermediates of glycolysis. Milder cases presenting primarily with
refeeding hypophosphatemia frequently go unrecognized [25]. Prevention of refeed-
ing syndrome by identifying patients at high risk prior to initiation of nutrition sup-
port and supplying carbohydrates gradually with close monitoring of electrolytes and
fluid status is critical.
While provision of nutrition support to malnourished patients has potential for
benefit in the ICU, it is crucial for nutrition to be prescribed meticulously, with close
monitoring of patients for signs of tolerance, change in clinical status, or potential
adverse effects (table 1). Efforts at avoidance of overfeeding, particularly when PN is
74 Schulman Mechanick
Table 1. Summary of risks, complications, and avoidance strategies associated with nutrition support in the ICU
Risk Potential complications Avoidance strategy
Underfeeding
Inadequate energy Protein calorie malnutrition
Infection
Prolonged mechanical ventilation
Use of indirect calorimetry or if unavailable aim for
2025 kcal/kg/day
Consider use of early SPN for high nutritional risk
patients
Greater than 100 g/day carbohydrate to avoid
starvation- related catabolism
Greater than 1 g/kg/week of lipid to avoid EFA
deficiency
Inadequate protein Protein calorie malnutrition
Sarcopenia
Diaphragmatic weakness
Aim for 1.21.5 g/kg/day or higher with hemodialysis,
burn or lack of response by clinical and biochemical
monitoring
Overfeeding
Excess energy
Excess carbohydrates Hyperglycemia
Hypertriglyceridemia
Fluid retention
Hypercapnia
Hepatic steatosis
Use of indirect calorimetry or if unavailable aim for
2025 kcal/kg/day
Close monitoring of glucose
Tight glycemic control with IIT
Monitor LFTs, triglycerides, respiratory status, fluid
status
Excess lipids Hypertriglyceridemia
Cholestasis
Immunosuppression
Fat overload syndrome
Maximum of 1 g/kg/day
Consider lipid- free PN in ACI
Monitor LFTs, triglycerides
Avoid in setting of bacteremia, fungemia
Excess protein Azotemia
Hyperammonemia in at- risk
patients
Hypertonic dehydration
Aim for 1.21.5 g/kg/day
Monitor BUN, sodium, ammonia, fluid status
Compensate for obligate renal free water losses
Refeeding syndrome Hypophosphatemia
Hypomagnesemia
Hypokalemia
Fluid overload
Multiorgan dysfunction
Risk stratification to identify high- risk patients
Close monitoring of electrolytes and fluid status
Slow titration of nutrition to goal
Compensate with increased phosphate and other
electrolytes
Feeding devices
Nasogastric tube, gastrostomy,
jejunostomy
Complications due to device
placement or dislodgement
Central line Infection
Thrombosis, bleeding
CLAB protocols
EFA = Essential fatty acid; LFTs = liver function tests; BUN = blood urea nitrogen; CLAB = central line- associated bacteremia.
Nutrition Support and ACI 75
used, are critical. Attention should be directed to all calories received by the patient
including dextrose- containing fluids or medications and lipid- based propofol infu-
sions. Rather than an initial a priori prescription and up- titration schedule, nutrition
support should be governed by a daily dialogue or interrogation of clinical data to
gauge the adaptive response to stress, non- Darwinian response to artificial nutrition,
and requisites to modify the nutrition support approach.
Controversies and Research Questions
Since the advent of various forms of nutrition support throughout the 20th cen-
tury, ideas regarding the optimal way to nourish critically ill patients have come
and gone. Following the initial popularity of PN, the preference of EN was realized,
attributed to preservation of gastrointestinal integrity and purported prevention
of bacterial translocation. A prevailing position that early (within 48 h) nutrition,
again preferably via the enteral route, should be the standard of care [2, 16, 26]
has been directly and indirectly challenged by recent hypotheses and clinical stud-
ies. Besides timing, issues regarding optimal delivery modalities, quantities, and
qualities of nutrition are also controversial. Formulating the clinical questions will
prove to be the toughest task as these questions are, for the most part, biased by
the clinical practice conditions of the researchers and dictums in the nutritional
literature.
Tight Glycemic Control or How Should Hyperglycemia Management Be Tailored in
Various Acute Critical Illness Patient Subsets?
Until relatively recently, hyperglycemia (blood glucose >200 mg/dl) was viewed as
either a beneficial etiologic component or an innocent marker of the stress response.
The proof- of- concept Leuven studies by Van den Berghe et al. [19, 27] demonstrated
that correcting hyperglycemia to near- normal blood glucose levels (80 110 mg/dl)
improved clinical markers and outcomes. These seminal studies introduced the con-
cepts of tight glycemic control and IIT. Subsequently, several studies, including the
Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm
Regulation (NICE- SUGAR) study [28], were unable to replicate the findings in the
Leuven studies. These discrepant results prompted a frenzy of editorials, commen-
tary, clinical practice guidelines amendments, and additional research protocols to
clarify the role of IIT. From a traditional component biology perspective, it seemed
clear that tight glycemic control confers net benefit, but only with more relaxed blood
glucose targets (140 180 mg/dl) [29, 30]. However, closer scrutiny of the dilemma
yields the following interpretations [31, 32]:
1 ICU culture plays a role: Leuven studies were conducted in a highly controlled
experimental setting while NICE- SUGAR was conducted in several diferent real-
life settings
76 Schulman Mechanick
2 Concurrent nutrition support modalities interact with the efect of IIT on
complex metabolic systems and eventual clinical outcomes: PN dampens
glycemic variability, which is independently associated with ICU mortality [33]
and preferentially used in Leuven- 1, but not Leuven- 2 or NICE- SUGAR
3 Concurrent quantities of nutrition support also interact with the efect of IIT:
median kcal/kg/day was higher in the Leuven studies than in NICE- SUGAR,
where patients were underfed.
Thus, from a systems perspective, tight glycemic control appears to be a neces-
sary, but not sufficient, component of metabolic support, i.e. both nutrition support
and metabolic control of glycemic status (mean blood glucose, glycemic variability,
and avoidance of hypoglycemia) appear to be necessary for net benefit in the ICU
[34]. Moreover, either one implemented alone, without the other, may potentially be
considered harmful. Even though the above question cannot currently be answered
specifically, the solution would involve clinical trials in specific patient subsets, incor-
porating factorial designs of both IIT and nutrition support protocols.
Supplemental Parenteral Nutrition or How Should Enteral Nutrition and Parenteral
Nutrition Support Be Optimally Delivered in Various Acute Critical Illness Patient
Subsets?
While EN is generally preferred, many ACI patients still cannot meet their nutrition
requirements. Supplemental parenteral nutrition (SPN) refers to the addition of PN
to EN, when necessary, to attain target nutrition. This is a contentious issue for many
since over the years PN has been vilified owing to an evidence base replete with PN-
dependent complications and failure to result in net benefit. As a result of differences
in ICU and general medicine cultures, as well as different interpretations of the medi-
cal literature, the recommended approach for SPN use differs across continents [34].
The American Society for Parenteral and Enteral Nutrition (ASPEN) clinical practice
guidelines [2] recommend withholding of SPN for the first 7 days in the ICU in pre-
viously healthy patients; this is based on a prioritization of randomized controlled
trials (RCTs) predominantly demonstrating PN net risks. The European Society for
Clinical Nutrition and Metabolism (ESPEN) clinical practice guidelines [16] recom-
mend SPN for all patients unable to reach target EN after 2 days; this is based on a
prioritization of prospective cohort studies predominantly demonstrating the benefit
of avoiding undernutrition. Canadian clinical practice guidelines, a joint venture of
several Canadian societies, advise consideration for SPN on a case- by- case basis once
all strategies to maximize EN have been employed [26].
Recently, the EPaNIC trial [35], a large multicenter RCT, sought to clarify the role
of SPN by comparing American (day 8) and European (day 3) timing of initiation,
in the setting of tight glycemic control. Results found the late initiation PN group to
have a median ICU length of stay 1 day shorter (3 vs. 4 days), reduced rate of infec-
tions and health care costs, and no difference in mortality. However, a close inspec-
tion of the study details questions the applicability of these results: (1) the majority
Nutrition Support and ACI 77
of the patients were not severely malnourished, with about 75% of patients having a
BMI of 20 30 (BMI <17 was an exclusion criterion); (2) the majority of the patients
had undergone elective cardiac surgery, with a low ICU mortality of 6%, and remain-
ing in the ICU a median of 3 4 days; (3) the nutritional risk score (NRS 2002) tool,
not validated in an ICU population, may have been unable to discriminate high- risk
patients; (4) patients in the early PN group received a large intravenous dextrose infu-
sion over the first 48 h, which is not the standard of care in most ICUs; and (5) target
energy intake was higher than (approaching 30 kcal/kg/day) and amino acid dosages
lower than (approaching 1.0 g/kg/day) recommended targets, without the use of indi-
rect calorimetry to substantiate requirements [36].
Further studies accounting for the above- mentioned factors should be pursued to
better clarify the role of SPN. Of note, a prospective RCT from Geneva [37] demon-
strated improved clinical outcomes with SPN, using indirect calorimetry for caloric
targets, added after ICU day 3 when EN is <60% of target, and in patients estimated
to stay more than 5 days in the ICU.
A potential area of interest that requires further study involves the interplay of
autophagy and PN in ACI. Autophagy, a protective pathway involving removal of
cellular debris and damaged organelles, is impaired by critical illness. Nutrients, par-
ticularly amino acids, may further attenuate autophagy when delivered parenterally
during ACI [38].
The recently described NUTRIC score, validated in the ICU population, may be
beneficial in future studies to select patients most likely to benefit from aggressive
nutrition support [39]. Volume- based EN protocols may enhance nutritional ade-
quacy and diminish the need for SPN [40].
In short, nutrition support should be viewed as part of an approach for an indi-
vidual ACI patient- based disease state, nutrition risk stratification, and potential for
adverse effects. The notion that all PN is the same should also be dispensed with.
Intravenous solutions with amino acids targeting a specific nitrogen threshold, dex-
trose minimized to avoid autophagy and overfeeding, and micronutrition to address
requirements, but without lipid admixtures, could provide a net benefit more so than
a simple dextrose- saline- based maintenance IV. Within the new landscape of tight
glycemic control and prevention strategies for central line- associated bacteremia,
these solutions, via nondedicated central venous access devices, with or without con-
current EN, may prove effective with future studies.
Energy and Protein Goals or What Are Reasonable Energy and Nitrogen Targets in
Various Acute Critical Illness Patient Subsets?
Accurate determination of protein and energy requirements in ACI patients has been
elusive. For energy, indirect calorimetry has been regarded as the gold standard, but
still suffers from multiple confounding factors and is not widely available. Nitrogen
balance studies using urinary collections are also espoused, but also confounded and
infrequently performed. Alternatively, predictive equations may be used, or simple
78 Schulman Mechanick
formulas, such as 20 25 kcal/kg/day and 1.2 1.5 g/kg/day protein. Observational
studies correlate hypocaloric nutrition (about 9 18 kcal/kg/day) with the best out-
comes [12]. Heyland et al. [41] recently showed the ease at which such observational
studies can be misinterpreted. In this prospective observational study, initial results
showed an increased mortality (OR = 1.28; 95% CI: 1.12 1.48) for patients receiv-
ing >2/3 versus <1/3 of prescribed nutrition. After adjusting for progression to oral
intake, the same group had a decreased mortality (OR = 0.67; 95% CI: 0.56 0.79,
p < 0.0001).
Consideration should be made for expanded use of indirect calorimetry when
available. The recent TICACOS study, a prospective randomized pilot trial, dem-
onstrated reduced hospital mortality with repeated measurements of indirect calo-
rimetry compared to use of 25 kcal/kg/day [42]. Thus, in ACI patients, target kcal
and nitrogen should be tailored to physiological tolerance based on organ function
and preferably guided by indirect calorimetry. Using the allostatic metabolic model
discussed above, it is argued that energy and nitrogen requirements may need to be
adjusted as patients migrate through different stages. At the present time, the impera-
tive is to determine optimal energy requirements taking into account sarcopenic body
composition changes and an empirically derived threshold for nitrogen provision.
Deviations from these nominal ranges would be expected to cause iatrogenic harm.
The question is at what point will this harm outweigh benefit.
Paradigm Change
The potential complications of nutrition support during ACI should not hinder its
use, but rather encourage a balanced and more individualized prescription. How can
this individualization be reconciled with a current movement toward standardization
of care in the ICU? The answer is with a change in focus from hard rules governing
nutrition support to a standardized approach that incorporates patient variability and
the need to interrogate and adjust from day to day.
In light of available data, we recommend beginning with nutritional risk strati-
fication on admission to the ICU. Use of an ICU- validated risk assessment tool
incorporating pre- existing malnutrition states, either extreme of BMI, status of the
gastrointestinal tract, and severity of disease, classifies patients as being at high or
low nutritional risk. Aggressive nutrition support, including use of early SPN consis-
tent with ESPEN guidelines and concurrent tight glycemic control protocols, should
be implemented for patients at high nutritional risk. Lower risk patients should still
receive all strategies to maximize EN with concurrent tight glycemic control proto-
cols, but may benefit from withholding SPN during the first ICU week, in accordance
with ASPEN guidelines. Frequent reassessment of clinical status, nutrition require-
ments, and biochemical data are critical to avoid overfeeding, underfeeding, and
other adverse effects.
Nutrition Support and ACI 79
Validation of this algorithm using large multicenter RCTs and Bayesian design
(a mathematical approach incorporating prior knowledge and beliefs to determine
experimental constraints) should be pursued. A systems approach may be instrumen-
tal in furthering research in this area. By evaluating the many interactions of ICU
nutrition support with other organ systems, medications, and clinical data, emergent
properties can be revealed.
Conclusions
Nutrition support, consisting of both adequate energy and protein, aims not only to
ameliorate losses of lean body mass, but also to attenuate the inflammatory milieu
of ACI and prevent accumulation of allostatic load in later stages of critical illness
when losses can no longer be offset. While suboptimal nutrition support certainly has
the potential for interference with recovery, it should not be abandoned out of fear.
Rather, a diligent analysis of individual risks and benefits should be realized (fig. 1).
Research efforts should be relevant to real- life settings, incorporate validated infor-
mation, and produce results that are practical.
Beneft > risk
Monitoring
- Dally reassessment
and ad[ustment
- Laboratory data,
cllnlcal status, nuld
status
Nutrltlonal components
- Lnergy
- Proteln
- Mlcronutrlents
Tlght glycemlc control
- Avoldance of hypoglycemla
- Mlnlmlze glycemlc varlablllty
- Provlde concurrently wlth
optlmal nutrltlon support
Poute of nutrltlon
- volume-based LN
when able (optlmlze
tolerance)
- SPN to meet needs
(can use llpld-free
solutlons vla
nondedlcated central
llnes)
- Tlmlng depends on
rlsk stratlcatlon
Amount of nutrltlon
- Avold underfeedlng
- Avold overfeedlng
- Use lndlrect calorlmetry
lf avallable
Nutrltlon rlsk assessment
- |CU-speclc tool
- |dentlfy hlghest rlsk patlents
Fig. 1. Approach to optimal nutrition support in ACI to maximize benefits and minimize potential
risks.
80 Schulman Mechanick
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Jeffrey I. Mechanick, MD
Division of Endocrinology, Diabetes, and Bone Diseases
Mount Sinai School of Medicine
1192 Park Avenue
New York, NY 10128 (USA)
Tel. +1 212 831 2100, E- Mail Jeffreymechanick@gmail.com
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 8289
Glucose Control
Jean- Charles Preiser
Department of Intensive Care, Erasme Hospital, Universit Libre de Bruxelles, Brussels, Belgium
Abstract
Stress- related hyperglycemia is a common finding in acutely ill patients, and is related to the sever-
ity and outcome of the critical illness. The pathophysiology of stress hyperglycemia includes hor-
monal and neural signals, leading to increased production of glucose by the liver and peripheral
insulin resistance mediated by the translocation of transmembrane glucose transporters. In one
pioneering study, tight glycemic control by intensive insulin therapy in critically ill patients was
associated with improved survival. However, this major finding was not confirmed in several other
prospective randomized controlled trials. The reasons underlying the discrepancy between the
first and the subsequent studies could include nutritional strategy (amount of calories provided,
use of parenteral nutrition), case- mix, potential differences in the optimal blood glucose level (BG)
in different types of patients, hypoglycemia and its correction, and the magnitude of glucose vari-
ability. Therefore, an improved understanding of the physiology and pathophysiology of glycemic
regulation during acute illness is needed. Safe and effective glucose control will need improve-
ment in the definition of optimal BG and in the measurement techniques, perhaps including con-
tinuous monitoring of insulin algorithms and closed- loop systems.
Copyright 2013 S. Karger AG, Basel
The interest for the metabolic changes associated with critical illness, and in par-
ticular the issue of hyperglycemia, has increased substantially over the last decade.
Before 2001, many studies reported that hyperglycemia [1] is an independent prog-
nostic marker of poor prognosis in acutely ill patients. A retrospective analysis of a
large heterogeneous population of critically ill patients found survival to be improved
when blood glucose (BG) was lowered to less than 150 mg/dl [2]. These retrospective
studies and many others suggested than lowering BG would improve the outcome of
critically ill patients. A landmark prospective study reported an impressive benefit of
tight glycemic control (TGC) [3] and is still fuelling many controversies and discus-
sions 10 years later.
This chapter intends to describe the reasons behind this ongoing controversy,
including the conduct and the results of the prospective trials. The physiological
regulation of BG, the mechanisms underlying stress hyperglycemia, and the issue of
insulin resistance will be discussed as well.
How Can Nutrition Interfere with Outcome?
Glucose Control 83
The Ongoing Controversy around Tight Glycemic Control
The landmark Leuven I trial [3] was a prospective randomized controlled study; in
essence this proof- of- concept study demonstrated that tight glycemic control (target
BG 80 110 mg/dl by intensive insulin therapy) improved survival and several second-
ary outcome variables [incidence of systemic infection, acute renal failure, need for
transfusions polyneuropathy, duration of mechanical ventilation, and length of stay
in the intensive care unit (ICU)]. However, several independent confirmatory studies
failed to reproduce these results [4 11]. In the largest of these confirmatory studies [9],
there was even a worsening of the vital outcome (90- day survival) in patients random-
ized to TGC. The design and case- mix of these confirmatory trials was similar, but
not identical. For instance, the target range of BG for the control (nonintensive insulin
therapy) group, the severity of disease at admission, the proportion of medical patients
and the sampling site for glycemic checks differed widely between studies (table 1); in
addition, the frequency of checks, the quality of glucose control assessed by various
Table 1. Characteristics of 8 prospective randomised controlled trials of TGC
Leuven I
[3]
Leuven II
[4]
VISEP
[6]
Glucontrol
[8]
Arabi
[5]
De la Rosa
[7]
NICE- SUGAR
[9]
COOIITSS
[10]
Subjects, n 1,598 1,200 488 1,078 523 504 6,022 509
Percentage
medical
0 100 46.9 40.4 83.2 48.8 62.9 87.2
Mean
admission
APACHE II/
SAPS II
9 23 20 15 23 16 21 60
Target BG
(control),
mg/dl
180200 180200 180200 140180 180200 180200 140180 standard
care
Mortality
Control
Intervention
10.9
7.2
30.1
29.9
25.9
24.7
15.3
18.7
13.6
16.9
32.4
36.6
20.8
22.3
42.9
45.9
Hypoglycemia
Control
Intervention
3.1
18.7
4.1
17.0
2.7
8.7
3.1
28.6
1.7
8.5
0.5
6.8
7.8
16.4
Allowed
sampling sites
A A A/C A/V/C A/C A/C A/V/C A
A = Arterial; V = venous; C = capillary.
84 Preiser
methods (for instance the time to reach the BG target, the proportion of time in band,
the hyperglycemic and hypoglycemic indices, the level of adherence to the insulin
algorithm, the interval between admission in the ICU and the start of insulin infusion,
and the type of insulin protocol used), the mean values of all BG readings, and the use
of a correction factor to convert whole BG concentration into plasma concentration
are available for only a minority of these studies and cannot be compared. However,
there was no consistent difference in the vital outcome (ICU mortality, hospital mor-
tality, and 28- day mortality) between the intervention and control arms [4 10]. The
results of the Leuven II [4] study were ambivalent, with an improved vital outcome in
the subgroup of long- stayers. Not surprisingly, TGC by intensive insulin therapy was
associated with a four- to sixfold increase in the incidence of hypoglycemia. In VISEP
[6] and Glucontrol [8], the rate of hypoglycemia and the mortality in the patients who
experienced at least one such episode (arbitrarily defined as a BG below 40 mg/dl)
were higher than in patients who did not experience hypoglycemia. An increase in
the mortality rate has also been associated with the occurrence of mild hypoglycemia
(BG below 81 mg/dl [12, 13]). In contrast, in both Leuven studies [3, 4], hypoglycemic
patients had no detectable differences in outcome when compared to patients without
any hypoglycemic episodes. These contrasting findings are consistent with the possi-
bility that long- lasting hypoglycemia, with consequent decreases in glucose availabil-
ity for tissues that are glucose- dependent, may be deleterious or even life- threatening.
Clearly, an accurate understanding of the consequences of hypoglycemia in critically
ill patients requires further investigation before large- scale implementation of TGC.
The issue of the amount of calories provided and the predominant route of nutri-
tion (enteral or parenteral) are critical, since the optimal BG level may not be identi-
cal in patients with different medical conditions or different caloric intake [11]. Total
parenteral nutrition (TPN)- related hyperglycemia is associated with increased mor-
tality [14], suggesting that glycemic control should be tighter in patients receiving
TPN. However, even when TGC is applied successfully, early high caloric intake by
TPN to complement insufficient enteral nutrition is associated with poorer outcome
than in the case of late TPN [15].
Current Recommendations
In parallel to the respective hopes and disappointments yielded by the Leuven I trial and
subsequent studies, clinical practice recommendations and guidelines moved from the
recommendation of a widespread implementation of tight glucose control in 2004 [16]
to the recent recommendation of avoidance of intensive insulin therapy to strictly con-
trol BG in nonsurgical and medical ICU patients with or without diabetes [17]. Updated
evidence- based guidelines issued by groups of experts involved in the care of critically
ill patients acknowledge that a universally acceptable threshold for BG can currently
not be defined, but that a BG target below 180 mg/dl is generally recommendable [18].
Glucose Control 85
Expert opinion and actual clinical practice commonly use an intermediate threshold to
start insulin therapy, most often 140 150 mg/dl [19]. These recent recommendations of
intermediate glycemic control essentially reflect that a tighter glycemic control cannot
be performed safely unless considerable technological improvements become available,
regardless of any theoretical and potentially relevant advantages of TGC. Indeed, clini-
cal practice and use of TGC reveals that this therapeutic strategy is more complex than
initially thought [20]. Several aspects of this complexity were unraveled by the discor-
dances between the results of the large prospective trials.
Regulation of Blood Glucose Concentration
An updated review on this topic has been published recently [21]. Briefly, the metab-
olism of carbohydrates is regulated by hormonal and neural signals, which modulate
glucose fluxes across cell membranes and the endogenous production. The transloca-
tion of glucose transporters (GLUT) is the prominent mechanism for the modula-
tion of glucose transport across the cell membranes [22]. The modulation of glucose
fluxes across cell membranes by the translocation of transporters is usually inter-
preted as an adaptive mechanism designed to supply sufficient amounts of glucose to
the noninsulin- mediated glucose uptake tissues. This mechanism is usually consid-
ered as adaptive since the provision of glucose to these noninsulin- mediated glucose
uptake tissues, including immune cells, brain, and kidney is indeed needed to survive
an otherwise lethal injury. GLUT- 1 is the predominant transporter for noninsulin-
mediated glucose uptake, and GLUT- 2 regulates the flow of glucose across liver cell
membranes. In contrast, after injury the insulin- mediated glucose uptake, mainly adi-
pose tissue and skeletal muscles, is less avid for glucose as a result of the downregula-
tion of the GLUT- 4 receptors. Together with the increase in glucose production, the
changes in the peripheral uptake of glucose lead to stress hyperglycemia [1].
Mechanisms of Stress Hyperglycemia
The magnitude and severity of stress hyperglycemia as well as the poor control of
glycemia during diabetes are associated with poor outcomes. However, the patho-
genetic mechanisms of type 2 diabetes mellitus and stress hyperglycemia are differ-
ent. In diabetes, the cause of hyperglycemia is a combination of insulin resistance
and defective secretion of insulin by pancreatic - cells. During stress hyperglycemia,
complex interactions between counterregulatory hormones (catecholamines, growth
hormone, and cortisol) and cytokines lead to excessive hepatic glucose production
and peripheral insulin resistance. This complex interplay and the respective roles of
increased insulin resistance and enhanced endogenous glucose production are largely
variable over time [1].
86 Preiser
Increased Glucose Production
The increase in hepatic output of glucose results from gluconeogenesis and to a lesser
extent from glycogenolysis. Gluconeogenesis is stimulated mostly by glucagon, and
to some extent by epinephrine and cortisol. Glycogenolysis is primarily triggered by
catecholamines and perpetuated under the influence of epinephrine and cortisol.
TNF- might promote neoglucogenesis by stimulating glucagon production, and the
inhibitory effects of insulin and of exogenous glucose on hepatic glucose production
are blunted. For these reasons, in the absence of severe malnutrition, the amount of
glucose produced by the liver and the other gluconeogenic organs during the 3 5
days after injury reaches 300 400 g/day (1,200 1,600 kcal/day).
Insulin Resistance
The common hallmark of stress hyperglycemia and type 2 diabetes mellitus is the
resistance to the effects of insulin on the metabolism of carbohydrates. A convenient
definition has recently been suggested for insulin resistance: the inability of insulin
to adequately stimulate glucose uptake into skeletal muscle or to inhibit gluconeogen-
esis in the liver [23]. In fact, during critical illness insulin resistance occurs abruptly,
within minutes or hours under the influence of stress hormones (catecholamines,
growth hormone, and cortisol), adipokines, and inflammatory mediators [24]. The
increase in peripheral resistance is characterized by the inability of skeletal muscles
and adipocytes to take up glucose, related to an alteration of insulin signaling and
with a downregulation of GLUT- 4 transporters. The magnitude of insulin resistance
is also related to the severity of the condition [25], although the values of insulin
resistance calculated by the hyperinsulinemic euglycemic clamp are widely scattered.
Interestingly, insulin sensitivity can be calculated using mathematical modeling,
allowing a more precise adaptation of the insulin infusion rate.
Goals of Glycemic Control during Critical Illness
The controversial data of interventional trials and the associations found between
hypoglycemia, hyperglycemia, high glycemic variability, and poor outcome of the criti-
cally ill patient progressively concurred to shift the concept of tight glucose control to a
therapeutic strategy able to minimize these three factors sometimes gathered under the
name of dysglycemia. Basically the U- shaped curve between admission glycemia and
outcome [2] suggests that the association with outcome is equally strong for hyper- and
for hypoglycemia. Still, whether hyper- /hypoglycemia represent markers of severity or
if these abnormalities mediate some adverse outcome is still partially unknown.
Risks Associated with Hypoglycemia
Hypoglycemia is the price to pay of TGC; it represents the major concern when start-
ing intensive insulin therapy and is the major cause of an increased medical and nurse
Glucose Control 87
workload. In the TGC studies, the metrics used to report hypoglycemia was the percent-
age of patients who experienced at least one episode of BG below 40 mg/dl. However,
mortality increases with the magnitude of hypoglycemia (defined as the lowest BG level
recorded). Recent data [12, 13, 26, 27] indicate that the relationship of mortality/hypo-
glycemia is already significant for moderate hypoglycemia (70 mg/dl), implying that the
clinical data recorded in the TGC studies should be re- examined. Physiologically, long-
lasting hypoglycemia will result in decreased in glucose availability for tissues in which
the uptake of glucose is concentration- dependent [26]. The most typical example is the
injured brain, and indeed the risks associated with hypoglycemia are mostly neurological
[27]. Clearly, an accurate understanding of the consequences of hypoglycemia in critically
ill patients requires further investigation before large- scale implementation of TGC.
Risks Associated with Hyperglycemia
In stress conditions, an overall massive glucose overload may happen, resulting from
the inhibition of the downregulation of GLUT transporters by proinflammatory medi-
ators, counterregulatory hormones, and hypoxia. At the cellular level, damage to mito-
chondrial proteins occurs and the formation of reactive oxygen species is increased
as a consequence of the shift from glycolysis toward accessory metabolic pathways.
At the tissue level, other effects of excess glucose concentrations include the exac-
erbation of inflammatory pathways, decreased complement activity, modifications
in the innate immune system, impairment in endothelial and hepatic mitochondrial
functions,

abolishment of the ischemic preconditioning, and protein glycosylation.
Clinically, hyperglycemia at admission has been associated with increased mortality
in various conditions [2]. During the ICU stay, the incidence of infectious complica-
tions and associated complications, including mortality, have also been linked to the
magnitude of hyperglycemia, namely after cardiac surgery [28].
Risks Associated with High Glycemic Variability
In addition to the risks of hyperglycemia and hypoglycemia, high glycemic variability has
also been associated with increased mortality in large retrospective cohorts of patients
[29, 30]. In vitro, or ex vivo, the effects of rapidly changing glucose concentrations in the
culture medium include increased oxidative stress and increased apoptosis. The clinical
implications of these findings are still poorly defined, namely because several differ-
ent metrics using data collected at variable time intervals were used to define glycemic
variability. Therefore, defining accurately and minimizing variability both seem to be
reasonable additional goals of future research in the field of glucose control.
Conclusions
In summary, much has changed in our approach to BG concentrations in critically
ill patients over the last decade. The Leuven studies encouraged us to pay greater
88 Preiser
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on tight glucose control by intensive insulin therapy
in adult intensive care units: the Glucontrol study.
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9 Finfer S, Chittock DR, Su SY, et al: Intensive versus
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10 Annane D, Cariou A, Maxime V, et al: Corticosteroid
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realization of the complexity of maintaining BG in a tight range. The development of
techniques to continuously monitor BG levels will help follow BG levels more closely,
and closed- loop systems by which insulin doses will be adjusted automatically accord-
ing to continuous BG readings and adapted to individual patient characteristics are
just over the horizon. Meanwhile, intermediate glycemic control currently appears to
be the safest option.
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Glucose Control 89
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Jean- Charles Preiser, MD, PhD
Department of Intensive Care, Erasme University Hospital
808 route de Lennik
BE 1070 Brussels (Belgium)
Tel. +32 25554756, E- Mail Jean- Charles.Preiser@erasme.ulb.ac.be
How Can Nutrition Interfere with Outcome?
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 9096
Glutamine
Mike Kim Paul E. Wischmeyer
Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colo., USA
Abstract
Glutamine (GLN) has been shown to be a key pharmaconutrient in the bodys response to stress and
injury. It exerts its protective effects via multiple mechanisms, including direct protection of cells
and tissue from injury, attenuation inflammation, and preservation of metabolic function. Data sup-
port GLN as an ideal pharmacologic intervention to prevent or treat multiple organ dysfunction syn-
drome after sepsis or other injuries in the intensive care unit (ICU) population. A large and growing
body of clinical data shows that GLN can be a life- saving intervention in well- defined critically ill
patient groups. Recent data has helped clarify that GLN shows the greatest benefit when adminis-
tered at doses greater than 0.35 g/kg/day, with optimal benefit potentially occurring at 0.5 g/kg/day.
Further, it appears that when possible GLN should be administered for longer than 5 days and more
ideally for the entire period of ICU or hospital stay. Finally, ongoing clinical trials may prove GLN
administration in the first 24 48 h following ICU admission and via both the enteral and parenteral
route are key to optimizing patient outcomes with this therapy.
Copyright 2013 S. Karger AG, Basel
Amino acid metabolism, particularly glutamine (GLN), increases in the critically ill
patient. In catabolic states, large amounts of GLN are released from muscle tissue [1]
as part of the bodys conserved evolutionary response to stress. Previous explanations
for the release of GLN in periods of stress include: use as a fuel source for rapidly
dividing cells, precursor for synthesis of nucleic acids, and role in renal acid buffer-
ing [2, 3]. Despite this massive release of GLN from muscle, it is well- described in
the literature that GLN levels are significantly decreased in critical illness, ultimately
leading to an increase in mortality in these patients [4, 5]. This indicates that humans
only have 24 48 h of GLN stores to maintain GLN levels following injury.
While GLN is classified as a nonessential amino acid and can be synthesized de
novo in states of health, it is now commonly described as a conditionally essential
amino acid, particularly in catabolic and stress states [6]. Recent data have revealed
that following illness and injury, GLN plays a vital role in inducing cellular protection
pathways, modulation of the inflammatory response, and prevention of organ injury
[5]. Recently, an editorial proposed four main hypotheses through which GLN exerts
Glutamine 91
its protective effects in critical illness, while indicating that further research is needed
to elucidate specific mechanisms. These mechanisms include improved tissue protec-
tion, immune regulation, preservation of glutathione and antioxidant capacity, and
preservation of cellular metabolism after injury [7]. Further, new data indicates that
GLN activates intracellular signaling pathways and regulates the expression of genes
related to signal transduction, apoptosis, and metabolism [8]. This data indicates that
the release of GLN from muscle is a stress signal to turn on genes vital to cellular
protection and immune regulation [5].
Mechanisms of Glutamine- Mediated Protection
Glutamine and Cellular/Organ Protection
It is well established that a central component of GLNs beneficial effects involves
induction of heat shock proteins (HSPs), specifically HSP- 70 [9 11]. Expression of
HSPs provides stress tolerance, protection from continued injury that could other-
wise cause cell death and/or impaired recovery [12]. The stress tolerance provided by
HSP- 70 can protect against cellular injury, lung injury, ischemia/reperfusion injury,
and septic shock [13]. Expression of HSP- 70 is dependent on adequate GLN concen-
trations. GLN- deficient critically ill patients appear to be incapable of generating an
adequate HSP response [14, 15].
Data from our laboratory has shown that GLN can induce HSP expression in in
vitro, in vivo, and clinical critical care settings. GLN induces HSP- 70 expression in
intestinal epithelial cells leading to protection against oxidant and heat injury [16].
Using heat shock factor- 1 knockout cells [10] and HSP- 70 knockout animals, we were
able to show that the capacity to express HSPs is required for GLN to protect against
cellular injury. Administering GLN to critically ill patients enhances HSP expression
and improves clinically relevant outcomes [17].
Glutamine and the Inflammatory Response
GLN has been shown to attenuate the release of proinflammatory cytokines following
illness/injury in both in vitro and in vivo models [18, 19]. Attenuation of the SIRS
response appears to correlate with improved survival after infection [20]. Using an
experimental model of infection after surgery, we found that acute early administra-
tion of GLN and the subsequent HSP induction can attenuate the acute hyperinflam-
matory response. The model also yielded a massive cytokine release that followed
injury or surgery. Specifically, the release of IL- 6 and TNF- is attenuated at 6 h
after surgery/injury. The mechanism of this reduced hyperinflammatory response
is GLN- mediated attenuation of nuclear binding/activation of NF- B [21]. In mod-
els of experimental sepsis, our laboratory found that 0.75 g/kg of GLN can attenuate
nuclear binding/activation of NF- B and prevent degradation of IB, its inhibitory
protein [21].
92 Kim Wischmeyer
Data exist showing that GLNs anti- inflammatory effect may be related to HSP
expression. Our laboratory has shown that HSP- 70 knockout mice do not demon-
strate the aforementioned attenuation of NF- B following GLN treatment, nor do
they exhibit attenuation of TNF- or IL- 6.
Glutamine and Immune Function
GLN influences immune cell regulation. Lymphocytes and macrophages metab-
olize GLN at a high rate. GLN is also necessary for the synthesis of purines and
pyrimidines, building blocks that are absolutely necessary when lymphocytes
or macrophages are activated. Expression of cell surface activation markers CD25
(IL- 2 receptor chain), CD45RO (leukocyte common antigen), and CD71 (transfer-
ring receptor) are dependent on the presence of GLN [22]. GLN is also required for
TNF- production [22].
Monocyte function is also hindered in the GLN- deficient environment. Altered
monocyte major histocompatibility complex class II is associated with postopera-
tive infection and sepsis and has been linked to expression levels of human leukocyte
antigen on the DR locus (HLA- DR expression) in cell studies [22].
Insulin Resistance and Hyperglycemia
Hyperglycemia and insulin resistance contribute to mortality in critical care. At least
one clinical trial of GLN in the intensive care unit (ICU) setting has observed that
GLN supplementation improved parameters of hyperglycemia and led to a significant
reduction in the number of patients requiring insulin [23]. A separate study set out
to study insulin resistance in trauma patients [24]. Forty patients were randomized
to receive either GLN (0.4 g/kg) or an iso- caloric/nitrogenous control. Insulin sen-
sitivity was measured via insulin clamp on days 4 and 8. It was found that the GLN-
supplemented patients had the most improved insulin sensitivity [24]. In light of this
data, it seems reasonable to conclude that some of GLNs beneficial effects may be
through insulin- dependent glucose metabolism.
Glutamine and Clinical Outcome in Critical Illness
In 2002, Novak et al. [25] reviewed all trials of GLN therapy in critical illness that
had been published until that time, and recent trials of GLN in critical illness have
since been added to this work (the updated meta- analysis is available at http://
www.criticalcarenutrition.com). According to the results of the new meta- analysis
(updated January 31, 2009), enteral or intravenous GLN significantly reduced mor-
tality (RR = 0.75, 95% CI: 0.61 0.93, p = 0.008) and infectious morbidity (RR = 0.79,
95% CI: 0.68 0.93, p = 0.005). GLN administration also led to an impressive 2.6 day
Glutamine 93
(95% CI 4.39 to 0.74, p = 0.006) decrease in ICU length of stay. In depth analysis
of the multiple (36) trials included in this analysis reveals that larger doses of GLN
(>0.3 g/kg/day) were most effective, and patients receiving parenteral (vs. enteral)
GLN received the most benefits. In the subgroup of patients requiring parenteral
nutrition, GLN led to a 29% reduction in the risk of death (RR = 0.71, CI: 0.55 0.92,
p = 0.008).
Very recent trials of GLN have shown conflicting results that appear largely related
to GLN dose and duration of treatment in critically ill patients. In 2011, Andrews et
al. [26] showed no benefit of short- term (approx. 5 days) GLN supplementation with
dosages of approximately 0.25 g/kg/day for men and 0.3 g/kg for women. However,
the benefits of GLN appear to be optimized with dosing at >0.35 mg/kg/day (with
optimal dosing likely occurring at 0.5 g/kg/day) and a length of treatment >5 days,
which has more consistently been shown to reduce mortality and infections in criti-
cally ill patients. Consistent with this emphasis on adequate dose and duration of GLN
therapy, the >400- patient Scandinavian GLN trial, also published in 2011, showed a
significant reduction in ICU mortality in the per protocol group [27]. Of note, in the
Scandinavian trial, the average length of GLN treatment in the per protocol group
was 12 days and the intention- to- treat group was 9 days, while the length of GLN
treatment in the trial by Andrews et al. [26] trial was approximately 5 days for the
GLN group. A final recent multicenter randomized controlled trial of GLN (approx.
0.35 g/kg/day) demonstrated a reduction in the occurrence of pneumonia and uri-
nary tract infections in patients in the GLN group [28]. In this study, 90% of patients
received GLN >5 days as part of the treatment period. In conclusion, GLN treatment
appears to consistently benefit critically ill patients when administered at an adequate
dose (0.35 0.5 g/kg/day) and for an adequate length of treatment (>5 days). Early
administration (within the first 24 28 h of admission to ICU) and higher acuity of
illness (approx. APACHE II >15) also may be important predictors of GLN benefit in
ICU patients [5].
Glutamine and Patients with Head Injuries
Until recently there has been little data related to GLN feeding and head injury. A
study from a research group in China studied the effect of parenteral alanyl- GLN
dipeptide (a more stable, soluble form of GLN available worldwide) on the clinical
outcomes of patients who have sustained severe traumatic brain injury. This large
randomized trial of 46 patients showed a reduction in gastrointestinal hemorrhage,
lung infection, and mortality in the group supplemented with GLN [29].
Berg et al. [30, 31] published two trials dispelling any concerns about GLN crossing
the blood- brain barrier and leading to increases in intracerebral levels of glutamate,
an excitatory neurotransmitter. These trials show that administering clinically rele-
vant doses of GLN to patients with head injuries did not alter intracerebral glutamate
94 Kim Wischmeyer
concentrations. Plasma GLN levels were increased after GLN infusion; however, no
changes were observed in microdialysate fluid glutamate concentration in the group
or in any individual patients [30].
Conclusion
GLN has been shown to be a key pharmaconutrient in the bodys response to stress
and injury. It exerts its protective effects via multiple mechanisms including direct
protection of cells/tissue from injury, attenuation of inflammation, and preserva-
tion of metabolic function. This data implicates GLN as an ideal pharmacological
intervention to prevent and/or treat multiple organ dysfunction syndrome following
sepsis or other injuries in the ICU population. This is supported clinically by a large
and growing body of data that demonstrates GLN can be life- saving in well- defined
critically ill patient groups.
The final answer as to whether or not GLN should be used routinely in the ICU
will come after the current ongoing clinical trials have been completed. The large
amount of mechanistic data and translational evidence on the use of GLN in the ICU
has led to increased funding of clinical trials of GLN. The Reducing Oxidant Stress
(REDOXS) trial group has begun clinical trials in Canada, the USA, and Europe
following an extensive published pilot trial that was completed in 2007 [32]. This
study implements a factorial design to examine the effects of GLN and antioxidants
on mortality in the ICU setting, and collects biological specimens to help elucidate
mechanistic pathways.
Currently, the clinical nutrition guidelines of every major nutrition and critical
care society give intravenous GLN a grade A recommendation for use in critically ill
patients requiring parenteral nutrition [33, 34]. Data from these societies and a cur-
rent meta- analysis indicates that clear mortality benefit occurs at larger dosing (more
than 0.35 0.5 g/kg/day of actual GLN) via intravenous administration [25]. Based
on clinical and laboratory data, lower doses of GLN are unlikely to provide benefit.
Doses below 0.35 0.5 g/kg will not serve to correct the marked GLN deficiency seen
in the critically ill. Lower doses have not been shown to induce the mechanistic ben-
efits hypothesized for GLNs benefits [11].
Thus, in ICU patients requiring parenteral nutrition, routine use of high-
dose (>0.35 g/kg/day) GLN therapy is now indicated. It should be emphasized
that treatment should be continued for >5 days and for the entirety of the ICU
stay. Additionally, early GLN administration at ICU admission and particularly
in higher acuity ICU patients with APACHE >15 should be prioritized. In other
patient groups, the large ongoing trials of GLN in critical illness will reveal if
the time will come for GLN to be recommended as standard of care for all ICU
patients.
Glutamine 95
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M, van der Spoel HJ, Zandstra DF: Plasma glu-
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PE: Effects of pharmaconutrients on cellular dys-
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14 Weiss YG, Bouwman A, Gehan B, Schears G, Raj N,
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15 Singleton KD, Serkova N, Beckey VE, Wischmeyer
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16 Wischmeyer PE, Musch MW, Madonna MB, Thisted
R, Chang EB: Glutamine protects intestinal epithe-
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17 Ziegler TR, Ogden LG, Singleton KD, et al:
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20 Chu EK, Ribeiro SP, Slutsky AS: Heat stress increases
survival rates in lipopolysaccharide- stimulated rats.
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22 Roth E: Nonnutritive effects of glutamine. J Nutr
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23 Dechelotte P, Hasselmann M, Cynober L, et al:
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26 Andrews PJ, Avenell A, Noble DW, et al: Randomised
trial of glutamine, selenium, or both, to supplement
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27 Wernerman J, Kirketeig T, Andersson B, et al:
Scandinavian glutamine trial: a pragmatic multi-
centre randomised clinical trial of intensive care
unit patients. Acta Anaesthesiol Scand 2011;55:812
818.
28 Grau T, Bonet A, Minambres E, et al: The effect of
L- alanyl- L- glutamine dipeptide supplemented total
parenteral nutrition on infectious morbidity and
insulin sensitivity in critically ill patients. Crit Care
Med 2011;39:1263 1268.
29 Yang DL, Xu JF: Effect of dipeptide of glutamine
and alanine on severe traumatic brain injury. Clin J
Traumatol 2007:145 149.
30 Berg A, Bellander BM, Wanecek M, et al: Intravenous
glutamine supplementation to head trauma patients
leaves cerebral glutamate concentration unaffected.
Intensive Care Med 2006;32:1741 1746.
31 Berg A, Bellander BM, Wanecek M, et al: The pat-
tern of amino acid exchange across the brain is
unaffected by intravenous glutamine supplementa-
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32 Heyland DK, Dhaliwalm R, Day A, et al: Optimizing
the dose of glutamine dipeptides and anitoxidants
in critically ill patients: a phase I dose- finding study.
JPEN J Parenter Enteral Nutr 2007;31:109 118.
33 McClave SA, Martindale RG, Vanek VW, 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 for Parenteral and
Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter
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34 Singer P, Berger MM, Van den Berghe G, et al:
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Paul E. Wischmeyer, MD, Professor of Anesthesiology
University of Colorado School of Medicine
12700 E. 19th Ave, Box 8602, RC2 P15- 7120
Aurora, CO 80045 (USA)
Tel. +1 303 724 4747, E- Mail Paul.Wischmeyer@ucdenver.edu
How Can Nutrition Interfere with Outcome?
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 97105
Leucine and Citrulline: Two Major Regulators
of Protein Turnover
Luc Cynober
a,b
Jean- Pascal de Bandt
a,b
Christophe Moinard
b
a
Clinical Chemistry Laboratory, Cochin and Hotel- Dieu Hospitals, AP- HP, and
b
Department of Experimental,
Metabolic and Clinical Biology, EA 4466, Paris Descartes University, Paris, France
Abstract
Both leucine and citrulline stimulate muscle protein synthesis, in part through a common mecha-
nism of action mediated by the mTOR signaling pathway. Both leucine- and citrulline- enriched
diets improve nutritional status in various experimental models of injury. However, in the context
of intensive care unit (ICU) patients, there is conflicting data on leucine and no data at all on citrul-
line. Therefore, beyond a strong rationale, large clinical studies are required before any reliable
recommendations can be issued on the use of leucine- or citrulline- enriched diets in ICU patients.
Copyright 2013 S. Karger AG, Basel
ICU patients lose muscle proteins, and this process is responsible for morbimortality
if excessively long or intense. Since an adequate nutrition program has been demon-
strated as first- line primary care in ICU patients (e.g. burn patients), researchers have
focused their attention on nutrients liable to curb protein loss. The list includes amino
acids such as branched- chain amino acids, mainly leucine and citrulline, as discussed in
this chapter, but also glutamine and arginine, along with other nutrients such as omega-
3 fatty acids and trace elements discussed elsewhere in this book. Clearly, none of these
nutrients is a magic- bullet cure, and if an ICU patient suffers from multiple organ fail-
ure, we are likely beyond the realm of any useful nutritional intervention. Nevertheless,
the administration of amino acids such as leucine or citrulline may offer valuable ben-
efits in stabilized ICU patients and possibly prevent secondary complications.
Leucine
Since the 1970s, when the regulatory role of branched- chain amino acids (BCAAs;
leucine, valine, isoleucine) in muscle protein metabolism was first demonstrated,
98 Cynober de Bandt Moinard
experimental studies have supported the view that BCAAs, specifically leucine, can
stimulate protein synthesis and decrease protein catabolism. This has prompted sev-
eral clinical studies designed to evaluate their potential value in catabolic situations
such as in intensive care unit (ICU) patients; however, as discussed below, most results
have failed to meet expectations.
Metabolism in Hypercatabolic Situations
Besides protein synthesis, BCAAs are metabolized by BCAA aminotransferase into
branched- chain keto acids (BCKAs) followed by oxidative decarboxylation by BCKA
dehydrogenase into ketogenic and/or gluconeogenic derivatives (fig. 1) [1].
The BCKA dehydrogenase complex is the key controlling step in BCAA catab-
olism, and it is stimulated by leucine. Excess leucine through this BCKA dehydro-
genase activation process could thus lead to valine and isoleucine deprivation. The
interconnectedness between these three amino acids makes it difficult to define the
exact mix of amino acids that needs to be supplied, and likely explains in part why
clinical results are not so conclusive.
BCAA degradation is closely related to energy metabolism. In stress situations,
BCAAs released by muscle protein catabolism are transaminated into BCKAs, which
once oxidized can provide up to 20% of the energy used by muscles [2], while their
amino group is used for alanine and glutamine synthesis [3].
BCAAs compete with aromatic amino acids for cellular transport via large neutral
amino acid transport system. Thus, variations in plasma BCAA concentrations are
CH
2
CH
3
CH
3
CH
COOH
CH
Leucine
-Methylpropionyl-CoA
Valine Isoleucine
-Methyl butanoyl-CoA
CH
3
CH
3
CH
NH
2
COOH
CH
NH
2
C
2
H
5
CH
3
C
2
H
5
CH
3
CH
NH
2
COOH
CH
CH CH
2 CH
CH
3
CH
3
CH COOH C
O
CH COOH C
O
C
2
H
5
CH
3
CH
O
CH
2
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH COOH C
O
CoA C ~ S CoA C ~ S CoA C ~ S
O O
Isovaleryl-CoA
-Keto butyrate -Keto isocaproate -Keto isovalerate
Propionyl-CoA
Acetyl-CoA
HMG-CoA
(Ketogenesis)
Succinyl-CoA
(Krebs cycle)
BCKA dehydrogenase
BCAA aminotransferase
Fig. 1. General aspects of BCAA metabolism.
Leucine and Citrulline 99
associated with an inverse variation in the transport of aromatic amino acids that, in
the brain, has been suspected to affect the metabolism of neurotransmitters such as
serotonin and catecholamines [4].
Rationale for Branched- Chain Amino Acid Enrichment of Nutritional Support
In contrast with most amino acids, leucine is poorly metabolized in the intestine
(10 15% of dietary leucine), and not at all metabolized by hepatocytes. For these
reasons, whereas BCAAs represent 20 25% of total amino acids in a protein meal,
they represent 40 50% of postprandial plasma enrichment. Nutrients given by the
parenteral route bypass the first splanchnic extraction. Therefore, a parenteral nutri-
tion solution should ideally contain 40 50% BCAAs rather than the 20 25% in solu-
tions currently on the market.
Of the three BCAAs, only leucine has been proven to be effective on protein
metabolism. On one hand, leucine acts on both protein catabolism and protein syn-
thesis. Its effect on protein catabolism requires leucine degradation since its keto- acid
derivative, - ketoisocaproate, is also effective. Leucine stimulates protein synthesis
mainly via activation of the mTOR (mammalian target of rapamycin) signaling path-
way. Despite longstanding debate as to whether the effects of leucine on protein syn-
thesis and degradation are similar in humans and rodents, recent studies in humans
have shown that leucine induces phosphorylation and activation of the mTORC1
complex and its downstream effectors S6 kinase 1 and 4E- BP1. The underlying mech-
anism remains to be clarified, although reports suggest the BCAA transport system,
system L, and/or several intracellular proteins such as phosphatidylinositol 3- kinase
hVps34, MAP4K3, and the Rag GTPases involved in response to variations in amino
acid availability play roles [5]. Of note, to date this BCAA- mediated effect on protein
synthesis seems to be only a short- term acute effect, as long- term efficacy has not
been clearly established.
On the other hand, BCAAs may also act on protein metabolism via their insulin-
secretory properties. Leucine and isoleucine induce insulin secretion [6], probably
mainly via a leucine- induced activation of glutamate dehydrogenase and thus ATP
production in islets of Langerhans - cells. Crucially, this effect decreases with ageing
[3]. In addition, some authors [2] have suggested that BCAAs could also act on pro-
tein metabolism via their contribution as nitrogen donors for glutamine synthesis.
Experimental Evidence
The ability of leucine to stimulate protein synthesis, inhibit proteolysis, or both, has been
established in a number of physiological or nonhypercatabolic pathological situations.
There has been debate over whether leucine keeps its anabolic properties in severe
injury [7], with recent studies demonstrating that leucine remains at least partly effec-
tive. In a model of chronic septic intra- abdominal abscess in rats, Vary [8] showed
that a single oral leucine administration is associated with an increase in the forma-
tion of mRNA- translation initiation complex, which contributes to improve protein
100 Cynober de Bandt Moinard
synthesis. The same group [9] observed that the effect of leucine on protein synthesis
was 50% decreased after lipopolysaccharide injection in mice and was abolished in
lipopolysaccharide- treated mTOR
/+
mice, thus reinforcing the idea that the mTOR
system plays a major role in leucine signaling.
Clinical Evidence
In burn injury, there are only three relatively dated studies available, with very limited
evidence of positive effects of BCAA supplementation (in [7]).
For surgical patients, as early as 1986, in a report of a research workshop on BCAA-
supplemented TPN in stress and injury, Brennan et al. (cited in [7]) concluded that
results from clinical trials were marginal and thus any evaluation remained superficial.
More recently, Choudry et al. [2] stated a number of small and diverse clinical trials
studied the effects of BCAA- enriched nutritional support in moderately- to- severely
stressed surgical and cancer patients. (...) The value of these trials is compromised by
small sample size, heterogeneous patients, poor study design, varying degrees of met-
abolic stress, and inappropriate endpoints. Interestingly, in a more recent crossover
study, Biolo et al. [10] compared the short- term effects of a BCAA- enriched TPN
(50%; Leu/Ile/Val: 1.3/1.1/1) against an isonitrogenous 25% BCAA- containing TPN
in 6 patients operated for colorectal or cervical cancer, and found that BCAA- enriched
TPN was associated with a 43% increase in muscle protein synthesis and a 2.7- fold
increase in glutamine flux. Sun et al. [11], in a prospective, randomized, double- blind,
controlled trial with 64 malnourished patients undergoing elective surgery for gastro-
intestinal cancer, found improved nutritional status and decreased morbidity with a
30% BCAA (Leu/Ile/Val: 1.5/0.9/1) solution compared to a 24% one.
In trauma patients, as for surgical patients, the poor quality and limited number
of studies available and most of all the heterogeneity of the patients included in these
studies (multiple trauma, surgery, etc.) make it difficult to draw reliable conclusions
[7].
Only two studies specifically addressed the utility of intravenous BCAA supplemen-
tation in sepsis (table 1). In 80 patients presenting peritonitis with accepted criteria
of sepsis, Jimenez Jimenez et al. (cited in [7]) showed improved nitrogen homeostasis
under BCAA supplementation. More recently, Garcia de Lorenzo et al. (cited in [7])
performed a multicenter, prospective, randomized trial on 69 ICU patients with sep-
sis with a 45% BCAA solution at two levels of nitrogen supply compared to a standard
(22.5% BCAA) solution. The authors did not observe any between- group differences
in terms of nitrogen balance, but they did find a significant reduction in mortality.
Both of these studies also reported a limited but significant improvement in short-
half- life visceral proteins in BCAA- supplemented groups only.
One last indication where BCAA supplementation has attracted recent interest in
an ICU context is liver surgery and transplantation. The long- known alterations in
BCAA availability during hepatic disorders and the more recently demonstrated pos-
sible influence of BCAAs on the production of hepatocyte growth factor [12] have
Leucine and Citrulline 101
prompted various studies into the benefits of BCAA in stressed patients with liver
disease.
In a randomized, controlled study of 124 patients undergoing surgery for hepato-
cellular carcinoma, Fan et al. [13] showed that a perioperative intravenous 35% BCAA
solution, compared to 5% dextrose, added to the oral diet for 14 days was associated
with a reduction in overall postoperative morbidity rate (34 vs. 55%), fewer septic
complications (17 vs. 37%), and better- preserved liver function. In the same set-
ting, Okabayashi et al. [14] showed that an oral perioperative supplementation with
a BCAA- enriched mixture was associated with lower postoperative complications
(17.5 vs. 44.4%) and shorter hospital stay (15.5 4.9 vs. 22.3 15.2 days). Further
studies showed improved insulin resistance [15] and postoperative quality of life [16]
with BCAA supplementation in this type of patient group.
In patients undergoing living donor liver transplantation, perioperative adminis-
tration of the same BCAA- enriched mixture has been demonstrated to improve met-
abolic status [17] and reduce the incidence of bacteremia [18].
Therefore, use of BCAA- enriched diet in ICU patients with liver disease is of great
potential value, but further large clinical studies are required in order to reach a firm
conclusion.
Several hypotheses can be put forward to explain these rather mitigated results.
First, as already mentioned, BCAAs share common membrane transport and meta-
bolic enzymes which could lead to cross- metabolism interference, and there is still no
clear definition of the proper ratio between the three BCAAs. Interestingly, Iresj et
al. [19] compared three different parenteral amino acid solutions in ICU patients and
found that even at high nitrogen supply, plasma leucine enrichment still decreased,
Table 1. BCAA administration in patients with sepsis
Treatment/control, n Dose and BCAA ratio TPN/duration Results
Jimenez
Jimenez et al.
40/40 45 vs. 22.5% 35 kcal/kg/day N balance
1.4/0.8/1
a
0.23 g N/kg/day visceral
proteins
15 days 3MH
Garcia de
Lorenzo et al.
22/25 45.5 vs. 22.5% 24 kcal/kg/day visceral
proteins
1.4/0.8/1 0.18 or 0.24 g
N/kg/day
mortality
(8 vs. 40.9%)
11 days
Both studies were detailed in [7]. N = Nitrogen; 3MH = 3- methylhistidine.
a
Leu/Ile/Val.
102 Cynober de Bandt Moinard
suggesting that these solutions do not supply enough leucine. However, in another
dynamic pharmacokinetic study in ICU patients, perfusion of a standard parenteral
nutrition solution was able to maintain leucine levels in plasma [20]. Thus, BCAA
requirements in ICU patients have yet to be defined. Second, and further complexify-
ing the determination of requirements, ICU patients are a heterogeneous population
in terms of BCAA status, with variations related to both nutritional status and under-
lying disease. Plasma BCAA levels tend to increase during protein- energy malnutri-
tion and decrease during pure protein malnutrition [21]. In stress situations, muscle
BCAAs can increase [22]. In sepsis, plasma BCAA levels can decrease, whereas mus-
cle BCAAs have been shown to either decrease or increase [3]. It is tricky to produce
a rationale for supplying extra leucine to patients who already have excess muscle leu-
cine, making it doubly important to identify the type of patients who would benefit
from an increased BCAA supply.
Citrulline
Metabolism in Hypercatabolic Situations
Several experimental and clinical studies converge on a clearly- described rapid
decrease in plasma citrulline concentrations in hypercatabolic states. This decrease
could be related to a decrease in production and/or an increase in consumption (to
sustain arginine requirements). One study [23] evaluating citrulline metabolism
(using stable isotopes) in healthy subjects, critically- ill patients, and septic shock
patients clearly demonstrated that whole- body citrulline production is significantly
reduced in ICU patients ( 26%), and totally depressed in septic patients ( 67%). The
consequence is a reduction of de novo arginine synthesis and nitric oxide (NO) pro-
duction in ICU patients. Since citrulline is produced in the gut, and in part from glu-
tamine [24], the hypoglutaminemia observed in these patients reduces gut availability
of glutamine for citrulline synthesis. The importance of the gut in hypocitrullinemia
in hypercatabolic states is confirmed by the fact that whole- body arginine production
is unaffected by the decrease in renal function (the kidney being the main site for
arginine synthesis) [23]. Moreover, the same authors [25] observed that the plasma
citrulline depletion was related to severity of inflammation in critically ill children
(i.e. where a negative correlation was observed between citrulline and CRP).
These findings raise the question of the potential utility of citrulline as a therapeu-
tic intervention in ICU patients since intestinal citrulline synthesis seems to be the
limiting step in arginine availability in ICU patients (see below).
Citrulline as a Marker of Intestinal Failure in Intensive Care Unit Patients
Given that citrulline is almost absent from food (with the notable exception of water-
melon), only exported by the intestine, and mostly catabolized in the kidneys, a
decrease in plasma citrulline emerged at the turn of the millennium as a promising
Leucine and Citrulline 103
marker of functional intestinal mass. Since then, the value of plasma citrulline as a
biomarker has been established in a large number of medical and surgical situations
where the gut is damaged (see [24] for the latest review on this topic).
Refocusing on ICU patients, there are still too few studies available. Supporting
the gut hypothesis of multiple organ failure, the excellent study by Piton et al. [26]
showed that low plasma citrulline was associated with a high grade of inflammation
(judged by CRP levels), nosocomial infection rate, and 28- day mortality in severely ill
(SAPS II = 50 18) and relatively old (60 16 years) ICU patients.
To date, two other studies performed in the Paris area (at R. Poincar and Cochin
hospitals) have been published, although in abstract form only. Both provide fairly
ambiguous results, with broad variability in patients with septic shock syndrome. The
usefulness of plasma citrulline as a biomarker in ICU patients therefore warrants fur-
ther larger studies [27].
Citrulline: A New Therapeutic Agent in Intensive Care Unit Patients?
There are two reasons why citrulline could be of interest in ICU patients. First, as
already mentioned, ICU patients are characterized by a hypocitrullinemia that is
proportional to disease severity, and consequently decreased arginine levels are also
observed. Because low citrulline production means low de novo arginine synthesis, it
would make sense to provide arginine in this situation. However, the use of arginine
remains controversial in ICU patients, in particular during sepsis, where an excessive
supply of arginine could spark overproduction of NO and thus lead to the hypoten-
sion responsible for septic shock and multiorgan failure. The interest of citrulline is
that it could be a good alternative to restore arginine homeostasis without any risk, as
the limiting step of arginine synthesis from citrulline is argininosuccinate synthase,
which is downregulated by nitrosylation [28]. This feedback mechanism of regulation
is a good way for NO to limit arginine availability in NO- producing cells, and this
system is ultimately efficient at limiting NO overproduction [26].
The second potential value of citrulline is its ability to modulate both muscle
mass and muscle function. In a model of protein- energy malnutrition in aged rats, a
citrulline- enriched diet improves muscle mass and maximal tetanic isometric force
[29]. Preliminary data obtained in the same model indicate that citrulline lowered
the expression of proteasome activator complex subunit 1 in muscle (Faure et al.,
unpubl. data). However, the effect of citrulline is not limited to aging. In a recent
paper, Le Plnier et al. [30] demonstrated that in adult fasted rats, citrulline is able to
improve muscle protein synthesis via mTORC1 activation [30]. In a very recent set of
experiments (performed in vitro), we clearly demonstrated that citrulline is a direct
modulator of the mTORC1 pathway (personal data) and confirmed that citrulline is a
major contributor to muscle homeostasis.
With regard to hypercatabolic states, there is no data available for ICU patients and
very few experimental studies on the potential benefits of citrulline supply during
injury. There are two experimental studies that have evaluated the ability of citrulline
104 Cynober de Bandt Moinard
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TC: Skeletal muscle protein balance in mTOR
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to preserve gut integrity. The first one demonstrated that citrulline is able to prevent
bacterial translocation after intestinal obstruction in mice [31], while the second one
showed that citrulline limits the impairment of intestinal microcirculation during
endotoxemia in the rat (Wijnands KA, et al., abstract form). Finally, a very recent
paper from Grisafi et al. [32] highlighted the ability of citrulline to limit vascular
alteration in a rat model of lung injury.
Acknowledgements
The authors thank Mrs. S. Ngon for her expert secretarial assistance. We apologize in advance for
not being able to cite all of the excellent works from colleagues due to space limitations.
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Prof. Luc Cynober, Pharm.D., PhD, Professor of Nutrition
Head of Department of Experimental, Metabolic and Clinical Biology and Research Unit EA 4466
Service de Biochimie, Hpital Cochin
27 rue du Faubourg- Saint- Jacques
FR 75014 Paris (France)
Tel. +33 0 1 58 41 15 91, E- Mail solange.ngon@cch.aphp.fr
Organ- Targeted Nutrition
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 106115
The Surgical/Trauma Patient
Arved Weimann
Klinik fr Allgemein- und Visceralchirurgie, Klinikum St. Georg gGmbH Leipzig, Leipzig, Germany
Abstract
In aiming for enhanced recovery and the reduction of postoperative morbidity, enhanced recovery
after surgery concepts have introduced a new era in perioperative management. It is frequently not
recognized that the enhanced recovery after surgery protocol does not overcome the necessity for
appropriate perioperative nutritional and metabolic care, particularly with those in intensive care.
Early detection and preoperative conditioning of patients at nutritional risk remains essential. In
patients at risk where inadequate oral intake is anticipated for a longer period, nutritional support
should be started early via the enteral route, possibly in combination with parenteral nutrition. For
early enteral nutrition in the intensive care unit, a slow increase in the administration rate is recom-
mended while observing the enteral tolerance by abdominal distension and gastric aspirate. While
the length of time before combining enteral and parenteral nutrition with the appropriate supple-
mentation is still under debate, immunomodulating substrates and diets have proven benefits in
surgical high- risk patients. Copyright 2013 S. Karger AG, Basel
In Nutrition therapy for the critically ill surgical patient: we need to do better!,
Drover et al. [1] showed that surgical intensive care patients received less nutrition
than medical patients, stating: Cardiovascular and gastrointestinal surgery patients
are at highest risk of iatrogenic malnutrition. The following review attempts to ana-
lyze and discuss the issue of nutrition therapy in surgical intensive care unit (ICU)
patients with regard to the current guidelines and the recent literature.
According to the prospective data from a multicentric observational study, in hos-
pitals most patients at risk will be found in the departments of surgery, oncology,
geriatrics, and intensive care medicine. The hospital complication rate is significantly
influenced by nutritional risk, severity of the disease, age >70 years, surgery, and can-
cer disease [2]. Just recently, lower food intake before hospital admission was shown
to be an independent risk factor for complication rate in patients undergoing abdomi-
nal surgery [3]. Bearing in mind the demographic development in the Western world,
surgeons will face an increase in the number of elderly patients at nutritional risk
undergoing major surgery for cancer.
The Surgical/Trauma Patient 107
Systematic assessment of risks, including nutritional risk screening, has been rec-
ommended for all patients on hospital admission. According to the guidelines of the
European Society for Clinical Nutrition and Metabolism (ESPEN), a severe metabolic
risk has to be considered with the presence of one or more of the following criteria
[4]:
1 Weight loss >10 15%
2 BMI <18.5
3 Serum- albumin <30 g/l (no hepatic or renal disease).
Indication for Nutritional Support
Despite the convincing and clear metabolic advantages of the enhanced recovery after
surgery concepts [5], there is still a considerable risk for hypocaloric nutrition and
delay of adequate nutritional support in non- identified metabolic risk patients and
those developing postoperative complications requiring intensive care.
The following recommendations are in accordance with the ESPEN guidelines
from 2006 and 2009 [5, 6]. Inadequate oral intake for more than 14 days is associated
with a higher mortality. Nutritional support is therefore indicated even in patients
without obvious undernutrition if it is anticipated that the patient will be unable to
eat for more than 7 days perioperatively. It is also indicated in patients who cannot
maintain oral intake above 60% of the recommended intake for more than 10 days. In
these situations, nutritional support (by the enteral route if possible) should be initi-
ated without delay. In case the tolerance to oral fluid and food intake is rather limited
for more than 4 days, it may be recommended to begin peripheral parenteral hypoca-
loric nutrition (e.g. two- chamber bag).
Preoperative Nutritional Strategies
In order to facilitate enhanced recovery after surgery, diminish the complication rate,
and avoid longer stays in the ICU, different concepts for improving patient nutritional
status, before major surgery are available. These are:
1 Substitution of caloric defciency in case of severe metabolic risk,
2 Metabolic conditioning (carbohydrate load),
3 Immunologic preconditioning.
Caloric Deficiency
It has remained unchanged that most patients will benefit from prompt surgery [5, 6].
In order to restore caloric deficiency, prolongation of surgery may only be reasonable
108 Weimann
in the case of undernutrition and severe metabolic risk. If nutritional support is indi-
cated, the enteral route should be preferred. Whenever possible, enteral nutrition
should be performed prior to hospital stay in order to avoid nosocomial infections
[6]. Parenteral nutrition is recommended in severely undernourished patients who
cannot be adequately orally or enterally fed. Usually, nutritional support is adminis-
tered for 7 14 days [5, 6].
Metabolic Conditioning
Preoperative fasting is unnecessary for most patients. Related to overnight fast-
ing, the metabolic burden of perioperative hypoglycemia has clearly been shown.
Preoperative carbohydrate drinks can be recommended for most patients without
significantly impairing gastric emptying. In the rare situation of patients who cannot
be fed by the oral/enteral route, a glucose infusion should be administered intrave-
nously [5, 6]. In several prospective randomized controlled trials (RCT), significant
advantages were shown in favor of carbohydrate loading. These included less post-
operative discomfort and shortened length of hospital stay after colorectal surgery.
However, a recent well- designed prospective RCT with 142 patients undergoing
open colorectal or liver surgery did not reveal any significant clinical advantage for
the carbohydrate drink. Only plasma cortisol level was significantly lower on post-
operative day 1, which could be related to stress reduction [7]. Other preoperative
drinks, which are additionally enriched with glutamine, are currently under investi-
gation [8]. In pancreatic surgery, preconditioning with glutamine, antioxidants, and
green tea extract versus placebo significantly elevated vitamin C levels and improved
total endogenous antioxidant capacity. However, oxidative stress and inflammatory
response were not reduced [9].
Immunologic Preconditioning
So- called immunonutrition refers to the use of formulas, enriched with arginine,
omega- 3- fatty acids, glutamine, and nucleotides.
Those who benefit most from these formulas are patients with obvious severe
nutritional risk, patients undergoing major cancer surgery of the neck (laryngectomy,
pharyngectomy) and of the abdomen (esophagectomy, gastrectomy, and pancre-
atoduodenectomy), as well as after severe trauma. This recommendation was recently
emphasized in the American Society for Parenteral and Enteral Nutrition (ASPEN)
Guidelines for critically ill adult patients [10]. Immune- modulating formulas contrib-
ute to a decreased rate of postoperative infections, and consequently to a decreased
length of stay in the hospital. This has been reconfirmed by the results of three recent
meta- analyses for surgical high- risk patients [11 13].
The Surgical/Trauma Patient 109
Whenever possible, administration of these immune- modulating formulas should
be started 5 7 days before and continued 5 7 days after surgery. In a recent prospective
RCT with patients after major abdominal cancer surgery, no advantages were found
for the administration of this formula when given only after surgery [14]. Therefore,
it is likely that patients will benefit most by preoperative supplementation. It remains
open whether future studies should focus on immunologic conditioning by pharma-
conutrition using single substances. In a recent single- substance prospective RCT,
high- risk patients undergoing esophagogastrectomy were compared, using omega- 3
fatty acid- supplemented enteral nutrition versus standard enteral nutrition for 7 days
before and after surgery. No difference was observed in morbidity and mortality or
HLA- DR expression on either monocytes or activated T lymphocytes [15].
Postoperative Nutrition
In general, interruption of nutritional intake is unnecessary. A recent meta- analysis
has clearly re- emphasised no increase of risk for developing anastomotic leakage after
surgery of the gastrointestinal tract [16]. When anastomoses of the upper gastroin-
testinal tract have been performed, early oral food intake is feasible and not harmful
to the patient, as shown by Hur et al. [17]. While no reasonable rationale exists for
longer periods of fasting, oral food intake should follow gastrointestinal tolerance. If
indicated, additional enteral nutrition can be delivered via a tube, with the tip placed
distally to the anastomosis [6].
Enteral Tube Feeding
Patients who benefit most from postoperative tube feeding are those who have just
had major cancer surgery to the abdomen and head and neck laryngectomy, pha-
ryngectomy, esophageal resection, gastrectomy, partial (pylorus preserving) pancre-
atoduodenectomy as well as those suffering from severe trauma. In these patients,
it may be reasonable to create safe enteral access via a nasojejunal tube or fine- needle
catheter jejunostomy at the time of surgery. It has been shown that for decompres-
sion after gastrectomy, nasojejunal tubes bear considerable discomfort for many
patients and may be unnecessary. For feeding reasons this favors fine- needle catheter
jejunostomy.
Ischemic bowel necrosis is an uncommon life- threatening complication which may
occur in cases of gastrointestinal intolerance, related to an inappropriately high enteral
feeding amount, especially when administered to the jejunum. The pathophysiology
of ischemic bowel necrosis is not fully understood. An own review of the literature
comprising 73 case reports between 1983 and 2008 revealed a high mortality of 68%
(40/73).
110 Weimann
Experimental studies support a plea for cautious enteral feeding in the situation of
hypotension and hemodynamic compromise under catecholamines. Minimal enteral
nutrition appears to be feasible even in patients with acute severe circulatory failure
[18]. A retrospective study in patients treated with vasopressors showed that those
who were enterally fed had a significantly lower mortality [19]. In cardiogenic shock,
Thibault et al. [20] recently hypothesized a positive effect on the integrity of the gas-
trointestinal barrier and the caloric needs by minimal enteral nutrition combined
with parenteral nutrition.
The following recommendations for critically ill surgical patients derive from
expert opinion. Enteral tube feeding can be started with low amounts (10 20 ml/h)
within 24 h after surgery. The feeding rate should be cautiously increased in stages
with special attention to jejunal application, e.g. 10 20 ml/h gradually increased in
stages over 4 days to 50 ml/h. In cases of hemodynamic instability, the administration
rate should be reduced to 5 10 ml or even stopped for a few hours. Gastrointestinal
tolerance has to be monitored, observing carefully gastric residual volume, the abdo-
men, and peristalsis. Prolonged gastric palsy may occur in surgical and trauma
patients and can be overcome by jejunal application. Diminished gastrointestinal tol-
erance due to impaired splanchnic perfusion has to be expected in case of elevated
serum lactate and procalcitonin [21]. Enteral feeding is also feasible in patients with
an open abdomen.
Indications for Parenteral Nutrition
Parenteral nutrition is indicated in undernourished patients in whom enteral
nutrition is not feasible or not tolerated [5]. Every pharmacological attempt
should be made to stimulate gastrointestinal motility. In the situation of impaired
gastrointestinal function and limited enteral caloric supply, it has been recently
intensively discussed whether parenteral nutrition should be started as early as
possible or after 7 days. In a large- scale multicenter prospective RCT, patients
with early parenteral nutrition had a significantly longer stay in the ICU [22].
While the observational data from Drover et al. [1] show a considerable caloric
deficiency in patients after gastrointestinal surgery, the ESPEN guidelines rec-
ommend the avoidance of longer delays when starting parenteral nutrition. In
those patients at risk, parenteral nutrition should be started within 2 3 days [23].
Surgical risk patients are always those in whom there is an indication for nutri-
tional support, and in whom >60% of energy needs cannot be met via the enteral
route, e.g. in high- output enterocutaneous fistulae, or in whom partly obstruct-
ing benign or malignant gastrointestinal lesions do not allow enteral refeeding
[5]. In order to avoid any time loss for appropriate caloric supply, it remains a
basic need for the intensivist to anticipate in patients at metabolic risk the period
of undernutrition.
The Surgical/Trauma Patient 111
Standardization
In most surgical patients, individualized nutrition seems to be unnecessary. Special
attention has to be attributed to patients with serious comorbidity [13]. Standardization
may follow a locally tailored enteral and parenteral feeding protocol. The advantages
of all- in- one solutions were shown with respect to feasibility, time and cost saving,
and the lower risk of contamination [23].
Caloric Amount
There is an ongoing discussion about the optimal caloric amount in the critically
ill [24, 25]. Singer et al. [26] recently presented data emphasizing an individualized
approach using indirect calorimetry. A standardized caloric target will be appropri-
ate in most ICU patients after major surgery without critical illness. The ESPEN
guidelines recommend 25 30 kcal/kg of ideal body weight (IBW) [5]. The recom-
mended rates of supply are: glucose 3 4 g/kg IBW (blood glucose level about 140
150 mg%), lipids 0.7 1.5 g/kg IBW (serum triglyceride <300 mg/dl), and amino
acids 1 1.5 g/kg IBW.
Vitamins and Trace Elements
In well- nourished patients who recover with oral or enteral nutrition within 5 days
after surgery, there is little evidence that intravenous supplementation of vitamins
and trace elements are required. A full range of vitamins and trace elements should
be supplemented on a daily basis in patients who after surgery are unable to be fed via
the enteral route, or to whom total or near total parenteral nutrition is required [5].
Vitamins and micronutrients should be administered separately.
Trauma
The general recommendations are not different for trauma patients. In this group of
patients, the benefits of early enteral nutrition have been clearly demonstrated in a recent
meta- analysis [26]. Bearing in mind that the gut is the motor for multiorgan failure,
enteral feeding should be started within 24 h with a low feeding rate (5 10 ml) adapted
to hemodynamic stability. A very recent well- designed multicenter study of 1,000
patients with acute lung injury, did not show any advantages for an initial lower amount
of trophic enteral feeding for the first 6 days (400 kcal) versus full enteral feeding (1,300
kcal) in terms of ventilator- free days, mortality, or infectious complications. However, a
favorable gastrointestinal tolerance was observed in the trophic group [27].
112 Weimann
Should laparotomy be indicated, and a longer period of nutritional support
anticipated, implantation of fine- needle catheter jejunostomy should be considered.
Otherwise, enteral feeding can be started via the nasogastric route. If there is gastric
palsy, a jejunal tube should be endoscopically positioned without delay [6]. In case
enteral nutrition should be required for more than 4 weeks, e.g. in severe brain injury,
the implantation of a percutaneous endoscopic gastrostomy must be considered.
Immunonutrition
Immune- modulating diets containing arginine, omega- 3 fatty acids and ribonucle-
otides can be safely recommended for trauma patients with an injury severity score
>18 and an abdominal trauma score >20 [6]. With regard to adverse effects in septic
patients, there is an ongoing discussion as to whether arginine and omega- 3 fatty
acids may be counteractive [28]. Including severe trauma patients with sepsis, own
data confirmed clinical advantages with regard to lesser incidence of systemic inflam-
matory syndrome (SIRS) and organ dysfunction.
As a single substance enteral, glutamine administration has proven effective for
trauma and burn patients [6].
Omega- 3 fatty acids in combination with antioxidants showed benefits in patients
with lung injury in two single- centered studies. Those with omega- 3 fatty acid-
supplemented nutrition had significantly more ventilator- free days and ICU- free
days than the control group. This led to guideline B recommendations for this group
of patients with lung injury and acute respiratory distress syndrome [29].
Very recently, the results of a randomized, double- blind, placebo- controlled, mul-
ticenter trial brought up considerable concerns [30]. Two hundred and seventy- two
patients were enrolled within 48 h of developing acute lung injury and treated in 44
hospitals of the US National Heart, Lung, and Blood Institute ARDS Clinical Trials
Network. The supplement with omega- 3 fatty acids, - linolenic acid, and antioxi-
dants was compared with an isocaloric control, and was separately administered from
enteral nutrition twice a day. The primary endpoint was the number of ventilator-
free days. Plasma eicosapentaenoic acid levels significantly increased in the treatment
group. However, the study was stopped early because the patients receiving the n- 3
supplement had significantly fewer ventilator- free days (14.0 vs. 17.2; p = 0.02) and
ICU- free days (14.0 vs. 16.7; p = 0.04). While 60- day mortality was nonsignificantly
higher in the n- 3 group, these patients had significantly more days with diarrhea.
The authors concluded that the n- 3 supplement could not improve the outcome of
patients with lung injury and may be harmful.
With regard to the parenteral administration of omega- 3 fatty acids, the current
guidelines state the optimal parenteral nutrition regimen for critically ill surgical
patients should probably include supplemental omega- 3- fatty acids [5] and fish
oil enriched lipid emulsions probably decrease length of stay in critically ill patients
The Surgical/Trauma Patient 113
1 Drover JW, Cahill NE, Kutsogiannis J, Pagliarello G,
Wischmeyer P, Wang M, Day AG, Heyland DK:
Nutrition therapy fort the critically ill surgical
patient: we need to do better. JPEN J Parenter
Enteral Nutr 2010;34:644 652.
2 Sorensen J, Kondrup J, Prokopowicz J, Schiesser M,
Krhenbhl L, Meier R, Liberda M, EuroOOPS
Study Group: EuroOOPS: an international, multi-
centre study to implement nutritional risk screening
and evaluate clinical outcome. Clin Nutr 2008;27:
340 349.
3 Kuppinger D, Hartl WH, Bertok M, Hoffmann JM,
Cederbaum J, Kchenhoff H, Jauch KW, Rittler P:
Nutritional screening for risk prediction in patients
scheduled for abdominal operations. Br J Surg 2012;
99:728 737.
4 Adamina M, Kehlet H, Tomlinson GA, Senagore AJ,
Delaney CP: Enhanced recovery pathways optimize
health outcomes and resource utilization: a meta-
analysis of randomized controlled trials in colorec-
tal surgery. Surgery 2011;149:830 840.
[23]. A recent meta- analysis for surgical patients confirmed these ESPEN- guideline
recommendations, showing significant advantages with regard to infection rate and
length of hospital and ICU stay [31].
With regard to immune- modulating total parenteral nutrition or near total paren-
teral nutrition, the supplementation of intravenous glutamine is recommended in the
guidelines [23]. This is supported by a recent meta- analysis [32]. No data are available
with regard to glutamine supplementation for combined enteral and parenteral nutri-
tion. Further input from prospective randomized trials is required.
Nutrition after Extubation
It has been shown that after extubation, many patients receive no more than 700 kcal/
day [33]. Reasons for this may include being in favor of oral feeding and artificial
nutritional support being stopped too early, especially in cases of discharge from the
ICU to the normal ward. Frequently, in many patients, oral intake from the normal
hospital diet is rather limited due to postcritical weakness and fatigue. These patients
have to be intensively encouraged and observed for oral food intake. Documentation
of the amount of oral intake is mandatory and supplementation with sip feedings may
be reasonable; in some cases enteral or parenteral support has to be reconsidered.
During this phase of recovery from catabolic critical illness, substrate tolerance
has been normalized with a metabolic shift to anabolism. From a nutritional point of
view, insufficient caloric supply in this period has to be considered a catastrophe. The
amount of administered calories should be 1.2- to 1.5- fold higher than the calculated
energy requirement.
In conclusion, yes we can do better in nutritional therapy in the critically ill sur-
gical and trauma patient. First of all, this means bringing the available evidence- based
guidelines into clinical practice.
References
114 Weimann
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Schetz M, Meyfroidt G, Van Cromphout S, Ingels C,
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Chesner M, Lev S, Grozovski E, Theilla M, Frishman
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Prof. Dr. Arved Weimann, MA
Klinik fr Allgemein-und Visceralchirurgie, Klinikum St. Georg gGmbH Leipzig
Delitzscher Strasse 141
DE 04129 Leipzig (Germany)
Tel. +49 341 909 2200, E- Mail Arved.Weimann@sanktgeorg.de
Organ- Targeted Nutrition
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 116125
Nutrition and Sepsis
Jonathan Cohen
a,b
W. Dat N. Chin
c
a
The Department of General Intensive Care, Rabin Medical Center, Campus Beilinson, Petah Tikva, and
b
The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel;
c
Division of Critical Care Medicine,
University of Alberta, Edmonton, Alta., Canada
Abstract
The effect of nutritional support in critically ill patients with sepsis has received much attention in
recent years. However, many of the studies have produced conflicting results. As for all critically ill
patients, nutritional support, preferably via the enteral route, should be commenced once initial
resuscitation and adequate perfusion pressure is achieved. Where enteral feeding is impossible or
not tolerated, parenteral nutrition (either as total or complimentary therapy) may safely be adminis-
tered. Most positive studies relating to nutritional support and sepsis have been in the setting of
sepsis prevention. Thus, the administration of standard nutrition formulas to critically ill patients
within 24 h of injury or intensive care unit admission may decrease the incidence of pneumonia.
Both arginine- supplemented enteral diets, given in the perioperative period, and glutamine-
supplemented parenteral nutrition have been shown to decrease infections in surgical patients.
Parenteral fish oil lipid emulsions as well as probiotics given in the perioperative period may also
reduce infections in patients undergoing major abdominal operations, such as liver transplantation.
There is little support at the present time for the positive effect of specific pharmaconutrients, in
particular fish oil, probiotics, or antioxidants, in the setting of established sepsis. More studies are
clearly required on larger numbers of more homogeneous groups of patients.
Copyright 2013 S. Karger AG, Basel
Sepsis may be defined as a predominantly cytokine- mediated, proinflammatory
response of the host to invading pathogens. The condition is characterized by
signs of acute inflammation, namely vasodilation, leukocyte accumulation, and
increased microvascular permeability, which occur at sites remote from the initial
infection. The incidence of sepsis is increasing worldwide, and is thought to be the
result of advancing age, immunosuppression, and multidrug- resistant infections
[1]. The immediate mortality rate is high, ranging from 20 to 50% and remains
elevated at 1- year among patients who survive. It is thus imperative that every
effort be made to prevent the onset of sepsis and provide effective therapy once
established.
Nutrition and Sepsis 117
The Pathophysiology of Sepsis
Sepsis occurs when proinflammatory mediators, released in response to an infection,
enter the bloodstream, resulting in the progression of a local infection to a more gen-
eralized response [2]. The proinflammatory mediators include TNF- and IL- 1, both
of which may cause fever, hypotension, and leukocytosis; induction of other proin-
flammatory cytokines; and the simultaneous activation of coagulation and fibrinoly-
sis. The inflammatory reaction is also capable of activating the synthesis of several
lipid mediators involved in the complex regulation of the inflammatory process,
including the regulation of gene expression and control of transcription factors.
Sepsis and the Gut
The gut is the largest immune organ in the body; therefore, events occurring at this
level may have significant effects on systemic immunity [3]. The circulatory abnor-
malities typical of sepsis, in particular decreased oxygen delivery to peripheral tis-
sues, may profoundly affect the normal barrier function of the gut [4]. The resulting
increased intestinal permeability facilitates translocation of bacteria and endotoxin
into the systemic circulation which may herald the development of multiple organ
dysfunction syndrome.
Interaction of Sepsis and Enteral Nutrition
The effects of sepsis may be amplified by the physiologic consequences of withholding
enteral nutrition (EN) from critically ill patients [3] (table 1). As a result of these pro-
cesses, macrophages are activated and prime circulating neutrophils in the microvas-
culature of the gut [5]. On reaching the systemic circulation, these neutrophils become
localized in distant organ sites, such as the liver or lungs. A second insult, such as
ischemia, sepsis, or shock, may result in their activation, leading to an exaggerated and
prolonged systemic inflammatory response and an increase in overall complications.
The Role of Nutrition in Sepsis
At the physiologic level, the provision of EN may be beneficial to the critically ill
patient [3], as shown in table 1. Whether this translates into improved clinical out-
comes, both in the prevention of new- onset sepsis and in the modulation of existing
sepsis, is presented below. Consideration is given to the effect of standard EN as well
as to enteral immunonutrition, a term used to identify formulas enriched with vari-
ous substrates to enhance or modulate the immunologic response. These immune-
118 Cohen Chin
modulating diets (IMD) contain substrates including specific fatty acids, arginine,
glutamine, antioxidants, and pre- or probiotics.
Feeding the Critically Ill Patient with Sepsis
As in all other critically- ill patients, provided the gastrointestinal tract is intact, the enteral
route is preferred. There is no evidence contraindicating the administration of EN in the
early stages of shock, and the reported incidence of intestinal ischemia associated with
EN is low [6]. However, since splanchnic perfusion may be compromised in hypotensive
patients, EN should probably be administered once initial resuscitation has been accom-
plished and an adequate perfusion pressure achieved. Parenteral nutrition may safely be
given where EN administration is not possible at all (total parenteral nutrition) or where
only inadequate protein/energy intake is possible (complementary parenteral nutrition).
The Role of Nutrition in Preventing Infections
Standard Enteral Nutrition
In a meta- analysis of six randomized controlled trials, the provision of standard EN
to medical and surgical critically ill patients within 24 h of injury or intensive care
Table 1. Physiological consequences resulting from withholding and providing EN (adapted from [3])
Physiological consequences induced by EN delivery Physiologic consequences of withholding EN
Maintains functional and structural integrity of intestinal
epithelium
Loss of functional and structural integrity of intestinal
epithelium resulting in opening of paracellular
channels between epithelial cells
Stimulates intestinal contractility so that bacteria is swept
downstream, controlling overall numbers
Reduced contractility promotes overgrowth of bacteria
Promotes role of commensal bacteria, which degrade
bacterial toxins and prevent colonization by pathogenic
organisms
Bacterial overgrowth of luminal pathogens,
e.g. Pseudomonas aeroginosa
Stimulates release of secretory IgA, which coats bacteria
and prevents adherence to epithelial cells
Barrier defense mechanism compromised by cytokine
release and apoptosis induced by bacteria attaching to
intestinal epithelium
Stimulates blood flow Decreased blood flow results in ischemia/reperfusion injury
Aids in processing nave CD4 helper lymphocytes by
exposure to bacterial antigens; invokes immune response
of tolerance
Nave CD4 helper lymphocytes proliferate along the
Th1 pathway generating proinflammatory effects
Nutrition and Sepsis 119
unit (ICU) admission has been shown to result in a statistically significant reduc-
tion in the incidence of pneumonia compared to a control group who received stan-
dard care, including EN provided later than 24 h [7]. No significant difference was
reported in the incidence of positive blood cultures in one trial of burn patients. It
should be stated that in this meta- analysis, no trials reported the incidence of sepsis
as an outcome.
Arginine- Supplemented Nutrition
Infections are the most frequent cause of morbidity after surgery and up to 54% of all
hospital- acquired infections occur in high- risk surgical populations. Arginine, a con-
ditionally nonessential amino acid, is vital in preventing T lymphocyte dysfunction
following physical injury [8], plays an important role in connective tissue repair, and
is the precursor for the formation of nitric oxide, an important signaling molecule.
Arginine deficiency occurs rapidly after physical injury (but not after sepsis) and is
related to poor intake together with the expression of arginase 1, which depletes argi-
nine. Studies to date suggest a substantial reduction in infectious complications asso-
ciated with the perioperative use of arginine- supplemented diets; no overall effect on
mortality was demonstrated [9]. Importantly, the largest treatment effect was most
apparent in the studies utilizing Impact, a formula containing arginine as well as
omega- 3 fatty acids.
Glutamine- Supplemented Nutrition
Glutamine, also a conditionally nonessential amino acid, is the primary fuel for rap-
idly dividing cells such as those in the gut. In this regard, gut integrity may be main-
tained even when delivered from the parenteral side of the intestinal epithelial cell.
Glutamine has important immune functions including improved tissue protection,
immune regulation, preservation of glutathione and antioxidant capacity, and the
preservation of cellular metabolism after injury [10]. During sepsis, glutamine deple-
tion may be severe and last longer than the generalized protein depletion associated
with the hypercatabolism after injury. A meta- analysis performed in 2002 demon-
strated that glutamine supplementation may be associated with a reduction in infec-
tious complication rates in surgical patients, especially when given parenterally and
in high doses [11]. A recent study reported a similar finding, namely a decrease in
the incidence of nosocomial infections, particularly nosocomial pneumonia and
urinary tract infection, following the administration of alanyl- glutamine dipeptide-
supplemented parenteral nutrition to critically ill patients in the first 3 days following
ICU admission [12].
Pre- and Probiotic Supplementation
The administration of prebiotics (fibers) and probiotics (living lactic acid bacteria)
may restore the physiological gut flora, prevent the multiplication of pathogenic
bacteria, decrease bacterial translocation, and enhance immune function [13].
120 Cohen Chin
Their administration to surgical patients undergoing high- risk abdominal opera-
tions (e.g. liver transplantation) and major trauma has been shown to lead to a
significant reduction in bacterial infection rates [14]. The results in patients with
acute pancreatitis remain controversial, with two trials showing a beneficial effect,
whereas a significantly higher mortality, largely related to bowel ischemia, was
noted in a third [14]. Their use in preventing infections in critically ill patients has
yielded conflicting results. Thus, in one study, their use was associated with a signif-
icantly delayed occurrence of secondary infections with Pseudomonas aeruginosa,
including respiratory colonization and/or infection [15]. However, in a more recent
study of mechanically ventilated patients who received prophylactic probiotics on
admission to ICU, no difference in the incidence of ICU- acquired infections was
noted, apart from fewer catheter- related bloodstream infections in the probiotic
group [16]. While a reduction of the 28- day mortality among severe sepsis patients
treated with probiotics was noted, their use was associated with a higher mortality
rate in nonsevere sepsis patients. These differences may be accounted for by the dif-
ferences in type and number of strains used, as well as time of initiation and dura-
tion of administration.
Omega- 3 Polyunsaturated Fatty Acid- Supplemented Nutrition
Omega- 3 polyunsaturated fatty acids (PUFAs), in particular eicosapentaenoic acid
(EPA) and docosahexaenoic acid which are found in high concentrations in fish oil,
have been a particular focus of nutritional research, due to their anti- inflammatory
mechanisms of action [17]. Thus, EPA incorporated into cell membranes replaces
arachidonic acid (omega- 6- PUFAs) as a substrate for the synthesis of eicosanoids;
these eicosanoids have a significantly lower inflammatory potential than those syn-
thesized from arachidonic acid. Omega- 3- PUFAs inhibit the production of proin-
flammatory cytokines such as TNF- , IL- 1, and IL- 6, and modulate the production
of IL- 10, an anti- inflammatory cytokine. Omega- 3- PUFAs may activate nuclear
receptor proteins which are antagonists of NF- B, responsible for the transcription
of genes involved in the inflammatory response, including cytokines and adhesion
molecules. Finally, omega- 3- PUFA- derived mediators, resolvins, inhibit the activa-
tion and migration of polymorphonuclear leukocytes during the resolution phase of
the inflammatory response, adding to their anti- inflammatory effects.
In clinical practice, the administration of a fish oil lipid emulsion combined with
parenteral nutrition has been shown to decrease the incidence of infectious morbidi-
ties following orthotopic liver transplantation [18]. In another study, a significantly
lower rate of infections, fewer complications, and a shorter length of hospital stay
was demonstrated in a group of 230 postsurgical patients who received parenteral
nutrition including fish oil for at least 3 days [19]. However, it should be stated that
while other studies in the surgical population have shown laboratory evidence of
immune modulation, they failed to show a clinical effect on the rate of infection
outcomes [20].
Nutrition and Sepsis 121
The Role of Nutrition in Critically Ill Patients with Established Sepsis
Omega- 3 Polyunsaturated Fatty Acids- Supplemented Enteral Nutrition
The literature regarding the effect of fish oil- supplemented diets in patients with
sepsis has yielded conflicting results. In a systematic review, Marik and Zaloga [21]
analyzed the literature to determine the clinical impact of IMD according to the
type of formula used (supplemented with arginine, arginine and glutamine, or argi-
nine and fish oil) and the patient setting. The majority of the formula contained
added antioxidants, in particular selenium, in varying concentrations. Twelve
studies included ICU patients: five with burn patients and seven with trauma
patients. Overall, the number of infections, especially secondary infections, was
significantly reduced in medical ICU patients with SIRS, sepsis, or acute respira-
tory distress syndrome who received supplemental fish oil. IMD had no effect on
mortality or length of stay. Interestingly, IMD supplemented with arginine with or
without additional glutamine or fish oil did not offer an advantage over standard
enteral formulas.
In support of these findings, a recent study demonstrated that the administra-
tion of EN enriched with EPA, - linolenic acid, and elevated levels of antioxidant
vitamins to patients with early sepsis developed less severe sepsis and/or septic
shock [22]. In addition, fewer patients developed cardiovascular and respiratory
failure or required invasive mechanical ventilation, and the number of days in
the ICU decreased. No significant differences in 28- day all- cause mortality were
observed.
In contrast to these studies, Grau- Carmona et al. [23] found no difference in
the incidence of nosocomial infections in septic patients with acute lung injury or
acute respiratory distress syndrome who received either an enteral diet enriched
with EPA, - linolenic acid, and anti- oxidants, or a standard enteral diet. In addi-
tion, the incidence of new- onset organ failures was not affected. The immune-
modulating effects of a fish oil- supplemented diet have also been challenged by the
lack of significant difference in bronchoalveolar lavage fluid or plasma biomark-
ers in mechanically ventilated patients with acute lung injury compared to saline
placebo [24]. Once again, no difference in outcomes was noted between the two
groups.
Alanine- Supplemented Nutrition
The administration of arginine supplementation has been linked to a potentially
increased mortality rate in hemodynamically unstable septic patients [25], which has
been attributed to increased levels of nitric oxide with augmentation of vasodilation.
Other studies, however, have shown a decreased rate of bacteremia and mortality in
septic ICU patients receiving arginine- containing diets [26]. More studies are needed
before any recommendation regarding the use and safety of arginine- supplemented
nutrition can be made.
122 Cohen Chin
Glutamine- Supplemented Nutrition
The administration of EN enriched with glutamine and antioxidants in septic patients
has been shown to improve parameters of multiple organ failure compared to a stan-
dard enteral diet [27]. However, the study group received a significantly higher pro-
tein supply, which may have affected the results.
Antioxidant- Supplemented Nutrition
Free radical production is increased during sepsis and this may result in the tran-
scription of genes involved in inflammation [28]. Antioxidant activity, which
is dependent on micronutrients including selenium, zinc, manganese, copper,
and iron, is depressed during critical illness, especially in the presence of sepsis.
However, in clinical studies, the administration of IV supplements did not decrease
the number of infections in patients with organ failure after complicated cardiac
surgery, major trauma, or subarachnoid hemorrhage [29], nor affected mortality in
patients with SIRS/sepsis treated with high- dose selenium supplementation alone
[30].
Parenteral Nutrition and Sepsis
Clinical studies have produced conflicting results.
Positive. In a large multicenter study, a significantly lower rate of infection and
shorter lengths of ICU and hospital stay were noted in patients receiving more than
0.05 g fish oil/kg/day (10% emulsion) than in those receiving less [31]. Mortality was
significantly decreased in those patients who received less than 0.1 g fish oil/kg/day.
The survival advantage was greater in some patient groups than others (severe head
injury > multiple trauma > abdominal sepsis > nonabdominal sepsis > postsurgery).
However, there were small numbers of patients in some groups and, in addition, this
study was not controlled or blinded.
Negative. In a randomized, controlled study performed on critically ill medical
patients, the administration of parenteral fish oil was not associated with a difference
in the rate of reduction of IL- 6 or HLA- DR (a marker of immune competence), or the
number of infections in patients compared to controls. In addition, other outcome
measures, including mortality, duration of mechanical ventilation, and length of ICU,
were similar in the two groups [32].
Conclusion
Studies performed in the setting of the critically ill patient, both in the prevention of
new- onset sepsis and the amelioration of established sepsis, have yielded conflict-
ing results. A number of reasons may be invoked to explain this [33]. First, the opti-
mal time of administration and dose of nutritional support have yet to be defined
in terms of the temporal pro- and anti- inflammatory patterns which characterize
Nutrition and Sepsis 123
1 Esper AM, Martin GS: Extending international sep-
sis epidemiology: the impact of organ dysfunction.
Crit Care 2009;13:120.
2 Cinel I, Dellinger RP: Advances in pathogenesis and
management of sepsis. Curr Opin Infect Dis 2007;
20:345 352.
3 McClave SA, Heyland DK: The physiologic response
and associated clinical benefits from provision of
early enteral nutrition. Nutr Clin Pract 2009;24:
305 315.
4 Hassoun HT, Kone BC, Mercer DW, Moody FG,
Weisbrodt NW, Moore FA: Post- injury multiple
organ failure: the role of the gut. Shock 2001;15:
1 10.
5 Jabbar A, Chang WK, Dryden GW, McClave SA:
Gut immunology and the differential response to
feeding and starvation. Nutr Clin Pract 2003;18:
461482.
6 McClave SA, Chang WK: Feeding the hypotensive
patient: does enteral feeding precipitate or protect
against ischemic bowel? Nutr Clin Pract 2003;18:
279 284.
7 Doig GS, Heighes PT, Simpson F, Sweetman EA,
Davies AR: Early enteral nutrition, provided within
24 h of injury or intensive care unit admission, sig-
nificantly reduces mortality in critically ill patients:
a meta- analysis of randomized controlled trials.
Intensive Care Med 2009;35:20182027.
8 Popovic PJ, Zeh HJ, Ochoa JB: Arginine and immu-
nity. J Nutr 2007;137(6 suppl 2):1681S 1686S.
9 Drover JW, Dhaliwal R, Weitzel L, Wischmeyer PE,
Ochoa JB, Heyland DK: Perioperative use of
arginine- supplemented diets: a systematic review of
the evidence. J Am Coll Surg 2011;212:385 399.
10 Preiser JC, Wernerman J: Glutamine, a life- saving
nutrient, but why? Crit Care Med 2003;31:
2555 2556.
sepsis. Second, critically ill patients represent a very heterogeneous population with
a variety of medical problems; therefore, large numbers of patients may be required
to demonstrate an effect. Third, in some studies, in particular those assessing the
effect of fish oil, control groups received a high- fat formula (n- 6), which may be
proinflammatory. Finally, formulas may differ substantially from one another in
composition, especially regarding supplemented vitamins and micronutrients,
potentially making it difficult to attribute the effect of a particular formula to
the substance under investigation (e.g. glutamine) rather than to the sum of the
formula.
Based on current knowledge, the following recommendations can be made:
1 Standard EN when started early, may have a role in preventing nosocomial
infections in critically ill patients
2 Arginine- supplemented diets given in the perioperative period may decrease
infections
3 Glutamine- supplemented parenteral nutrition may reduce infections in surgical
patients
4 Probiotics given in the perioperative period may reduce infections in patients
undergoing major abdominal operations
5 Fish oil- supplemented parenteral nutrition may have a role in reducing
postoperative infections in patients undergoing major abdominal surgery, such as
liver transplantation; however, more studies are required
6 To date there is no consistent evidence that the addition of fsh oil, probiotics, or
antioxidants positively afects outcome in patients with established sepsis.
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124 Cohen Chin
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22 Pontes- Arruda A, Martins LF, de Lima SM, Isola
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25 Bertolini G, Iapichino G, Radrizzani D, et al: Early
enteral immunonutrition in patients with severe
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ized multicentre clinical trial. Intensive Care Med
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26 Galban C, Montejo JC, Mesejo A, Marco P, Celaya S,
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27 Beale RJ, Sherry T, Lei K, Campbell- Stephen L,
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Schneider H: Early enteral supplementation
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29 Berger MM, Soguel L, Shenkin A, Revelly JP, Pinget
C, Baines M, Chiolro RL: Influence of early anti-
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Prof. Jonathan Cohen
Department of General Intensive Care, Rabin Medical Center
Campus Beilinson
IL 49100 Petah Tikva (Israel)
Tel. +972 3 9376524, E- Mail jonatanc@clalit.org.il
Organ- Targeted Nutrition
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 126135
The Renal Failure Patient
Wilfred Druml
Department of Medicine III, Division of Nephrology, Medical University of Vienna, Vienna, Austria
Abstract
Renal failure patients comprise a heterogenous group of subjects with widely differing meta-
bolic patterns and nutritional requirements. These disease states include acute kidney injury
(AKI), acute- on- chronic renal failure, chronic kidney disease, and regular hemodialysis therapy.
Renal failure per se is associated with a broad spectrum of specific metabolic alterations;
presents a panmetabolic disease process; and, especially in the case of AKI, induces a
proinflammatory, pro- oxidative, and hypercatabolic state which exerts a profound impact on
metabolism and morbidity/mortality. Besides the metabolic alterations induced by renal dys-
function and the often underrated/forgotten profound impact of renal replacement therapy,
metabolism is also affected by the underlying disease process requiring intensive care unit ther-
apy, other organ failures, and complications especially infections. Certainly, nutrition support
is not fundamentally different from other disease processes, but these variations in metabolism
and nutrient requirements have to be considered when designing a nutrition regimen. Nutrition
needs can differ widely between patients, as well as in the same patient during the course of
disease. Thus, even more than in other subjects, the patient with renal failure requires an indi-
vidualized approach in nutrition support, and because of the altered metabolism of many nutri-
ents and intolerances for electrolytes and volume, the nutrition support in patients with renal
failure requires much closer monitoring than in other disease states.
Copyright 2013 S. Karger AG, Basel
The renal failure patient certainly presents one of the most challenging problems of
nutrition support in the intensive care unit. Patients with renal failure comprise a
heterogeneous group of patients with complex metabolic environments and broadly
varying nutritional needs.
These patients include subjects with acute kidney injury (AKI), the rapidly increas-
ing group of subjects with acute- on- chronic kidney injury, and in an aging popula-
tion the many patients with chronic kidney disease, as well as those on regular renal
replacement therapy (RRT).
The metabolic situation is not only affected by renal dysfunction and the
type and intensity of RRT, but also by the underlying disease process and
Renal Failure Patient 127
associated complications. Nevertheless, renal failure per se is associated with
a broad spectrum of specific metabolic alterations. In particular, AKI induces
a proinflammatory, pro- oxidative, and hypercatabolic state which exerts pro-
found impact on metabolism and morbidity/mortality [1, 2]. Moreover, it is
increasingly recognized that the various RRT exert a profound impact on metabo-
lism and nutrient balances which have to be considered in designing nutrition
support [3].
Taken together, nutritional requirements can fundamentally differ between
patients, but can also vary considerably in the same patient during the course
of disease. In general, nutrition support is not principally different from other
patients; however, in designing a nutrition regimen for a patient with AKI, the
altered metabolism and nutrient requirements have to be considered. Furthermore,
nutrition must be closely adapted with fluid and electrolyte management, and
has to be coordinated with RRT. Thus, much more than in other subjects, the
patient with renal failure requires an individualized approach in nutrition sup-
port. Moreover, altered metabolism and intolerances for electrolytes and volume
nutrition support requires a much closer monitoring than in other disease states
[4].
The Metabolic Environment and Nutritional Requirements in Patients with Renal
Failure
Renal dysfunction may present as a complication occurring within a broad
spectrum of underlying pathologies. In the case of AKI, clinical presenta-
tion may range from uncomplicated mono- organ failure in a noncatabolic
patient to a critically ill patient with multiple organ dysfunction syndrome.
Thus, metabolic changes will be determined not only by renal failure, but also
by the underlying disease process and/or additional complications and organ
dysfunctions.
Nevertheless, renal failure in addition to the obvious effects on water, electro-
lyte, and acid- base metabolism affects all metabolic pathways of the body with spe-
cific alterations in protein and amino acid, carbohydrate, and lipid metabolism, and
can induce a proinflammatory, pro- oxidative, and hypercatabolic state (table 1).
Moreover, the type and intensity of RRT exert profound effects on metabolism and
nutrient balances.
The optimal intake of nutrients in patients with renal failure is mainly influ-
enced by the nature of the illness causing renal dysfunction, the extent of catab-
olism and type, and frequency of RRT. Again, renal failure patients comprise a
heterogeneous group of subjects with widely differing nutrient requirements, and
it must be noted that these can vary considerably in the same patients during the
course of disease.
128 Druml
Energy Metabolism and Energy Requirements
In patients with uncomplicated renal failure, energy expenditure is within the range
of healthy subjects and, thus, energy requirements are determined by the underly-
ing disease/associated complications [5]. Patients with renal failure should receive
20 30 kcal/kg BW/day. Even in hypermetabolic conditions such as sepsis or mul-
tiple organ dysfunction syndrome, energy expenditure is rarely higher than 130%
of calculated basic energy expenditure, and energy intake usually should not exceed
25 30 kcal/kg BW/day [6].
Carbohydrate Metabolism
Hyperglycemia is frequently present in patients with renal failure, with the major
cause being insulin resistance. A second feature is stimulated hepatic gluconeogen-
esis, mainly from conversion of amino acids released during protein catabolism that
cannot be suppressed by exogenous glucose infusions [7].
Hyperglycemia in the critically ill has been recognized as an important determi-
nant in the evolution of complications such as infections or organ failures (especially
AKI) and prognosis [8]. Thus, avoiding hyperglycemia must be strictly observed dur-
ing nutritional support (blood glucose target: 110 150 mg/dl), and insulin require-
ments are usually higher in patients with AKI [9].
Lipid Metabolism
Profound alterations of lipid metabolism occur in patients with renal failure which
result in hypertriglyceridemia, the major cause being an impairment of lipolysis [10].
Table 1. Important metabolic abnormalities induced by renal failure
Induction/augmentation of an inflammatory state
Impaired immunocompetence
Activation of net protein catabolism
Peripheral insulin resistance/increased gluconeogenesis
Inhibition of lipolysis and reduced clearance of plasma fat
Depletion in the antioxidant system
Metabolic acidosis
Impaired potassium tolerance
Reduced vitamin D activation
Other endocrine abnormalities: hyperparathyroidism, erythropoietin resistance,
resistance to growth factors, etc.
Renal Failure Patient 129
This is in sharp contrast to other acute disease states in which lipolysis is usually aug-
mented. Fat particles of artificial lipid emulsions for parenteral nutrition are degraded
similarly to endogenous VLDL, and impaired lipolysis in renal failure also retards the
elimination of intravenously infused lipids. Relevant for enteral nutrition, it should be
noted that intestinal lipid absorption is also retarded in renal failure [11].
Protein and Amino Acid Metabolism/Protein Requirements
AKI is characterized by an activation of protein catabolism and a sustained negative
nitrogen balance [12]. The causes of hypercatabolism are complex and manifold, and
present a combination of unspecific mechanisms induced by the acute disease pro-
cess and underlying illness/associated complications, with specific effects induced by
the loss of renal function and by the type and intensity of RRT [13].
Several catabolic factors are operative in patients with renal failure. Insulin resis-
tance, metabolic acidosis, the release of inflammatory mediators such as TNF- , the
depletion of antioxidative factors, the secretion of catabolic hormones, hyperparathy-
roidism, suppression and/or decreased sensitivity of growth factors, and the release of
proteases from activated leucocytes can all stimulate protein breakdown. Moreover,
RRT causes a loss of amino acids and protein, and may stimulate protein catabolism.
Last but not least, inadequate nutrition contributes to the loss of lean body mass in
AKI. Starvation can augment the catabolic response and malnutrition has been iden-
tified a major determinant of morbidity and mortality in AKI.
Amino Acids and Protein Requirements
The optimal intake of amino acids/protein continues to be the most controversial ques-
tion relating to nutritional support in critically ill patients with renal failure, especially
those with AKI. In patients on continuous renal replacement therapy (CRRT), the pro-
tein catabolic rate accounts on average for 1.4 1.7 g/kg BW/day and an amino acid/
protein- intake of 1.4 1.7 g/kg BW/day has been recommended, which includes amino
acid/protein losses induced by RRT [4, 14]. Recently, some authors have suggested an
even higher amino acid intake of up to 2.5 g/kg BW/day for patients with AKI [15].
However, there are no proven advantages of such excessive intakes, which can increase
uremic toxicity and provoke metabolic complications such as hyperammonemia.
Metabolism and Requirements of Micronutrients
Serum levels of water- soluble vitamins are usually low in renal failure patients mainly
because of losses induced by RRT, and thus requirements are increased. Intake of
130 Druml
ascorbic acid should be kept below 250 mg/day because any excessive supply may
precipitate secondary oxalosis.
Despite the fact that there are no relevant losses during RRT, plasma concentra-
tions of lipid- soluble vitamins A, D and E, but not of vitamin K are decreased in
patients with AKI [16].
Many alterations of trace element homeostasis are a reflection of an unspecific acute
phase response with redistribution of trace elements within the body. Selenium levels are
profoundly decreased and this is augmented by CRRT- associated selenium losses [17].
Several micronutrients are important components of the organisms defense mecha-
nisms against oxygen free radical- induced injury. A profound depression in antioxidant
status has been documented in patients with AKI, and an adequate supplementation of
micronutrients to meet the increased requirements must be strictly observed [18].
Electrolytes
Derangements in electrolyte balance in patients with renal failure are affected by a
broad spectrum of factors in addition to renal dysfunction, residual renal function,
and urine output, including the type of underlying disease and degree of hyperca-
tabolism, type and intensity of RRT, and drug therapy, as well as the timing, type, and
composition of nutritional support.
Electrolyte requirements do not only vary considerably between patients, but can
vary during the course of the disease. In nonoliguric patients, in subjects on CRRT, and
during the polyuric phase of AKI, electrolyte requirements can be considerably altered.
RRT- associated phosphate losses have to be replaced. Thus, electrolyte requirements
have to be evaluated on a day- to- day basis and intake has to be adjusted frequently.
Metabolic Impact of Extracorporeal Therapy
The impact of intermittent hemodialysis on metabolism is manifold. Several water-
soluble substances such as amino acids, vitamins, and carnitine are lost during
hemodialysis. Protein catabolism is not only caused by amino acid losses, but also by
activation of protein breakdown. Moreover, it has been suggested that generation of
reactive oxygen species is augmented during hemodialysis (table 2).
CRRT, the preferred treatment for patients with AKI, is also associated with a broad
pattern of metabolic consequences, which may become especially relevant because of
the continuous mode of therapy and associated high fluid turnover of up to more
than 60 l/day (table 2).
A major effect of CRRT is the elimination of small- and medium- sized molecules.
Amino acids losses can be estimated from the volume of the filtrate and the average
plasma concentrations (on average approx. 0.2 g/l filtrate). Depending on the filtered
Renal Failure Patient 131
volume, total loss is 5 15 g amino acids/day, representing about 10 15% of amino
acid intake. Depending on the type of therapy and the membrane material used, addi-
tional losses of protein can account for up to 20 g/day.
Water- soluble vitamins, such as thiamine, folic acid, vitamin B
6
, and vitamin C,
are also eliminated during CRRT, and an intake above the recommended dietary
allowance (RDA) is required in these patients [19]. Moreover, selenium losses during
CRRT can account for twice the RDA [17].
Phosphate losses during RRT using phosphate- free dialysate/substitution fluids
are considerable and may affect prognosis [20]. Care has to be taken to avoid evolu-
tion of hypophosphatemia during RRT and nutrition support.
Nutrient Administration
General Considerations
The practice of nutrition support in critically ill patients with renal failure is not fun-
damentally different from that in patients without renal dysfunction. However, as
Table 2. Metabolic effects of RRT
Intermittent hemodialysis
Loss of water- soluble molecules
Amino acids
Water- soluble vitamins
Carnitine
Other
Activation of protein catabolism:
Loss of amino acids/proteins/blood
Induction of inflammation/cytokine- release (TNF- , etc.)
Inhibition of protein synthesis
Increase in reactive oxygen species production
Loss of electrolytes (phosphate, magnesium)
Continuous renal replacement therapy
Heat loss
Excessive load of substrates (lactate, citrate, glucose)
Loss of nutrients (amino acids, vitamins, selenium, etc.)
Loss of electrolytes (phosphate, magnesium)
Elimination of peptides/proteins (hormones, mediators?)
Consequences of bioincompatiblity
Induction/activation of mediator- cascades
Induction/activation of an inflammatory reaction
Stimulation of protein catabolism
132 Druml
detailed above, the nutritional regimen has to be adapted to the altered metabolism
and nutrient requirements, and has to be coordinated with RRT.
Nutrient requirements in intensive care unit patients with renal failure are sum-
marized in table 3. The optimal intake of nutrients in these patients is influenced
more by the nature of the acute illness, the extent of catabolism, and type and fre-
quency of RRT, than by renal dysfunction. Again, it must be noted that patients with
renal failure present a heterogeneous group of subjects with widely differing nutrient
requirements, which may differ considerably between individual patients and may
fundamentally vary also during the course of disease. An individual daily assessment
of nutrient requirements is mandatory.
Patients with AKI- RIFLE Stage R and I/AKIN Stages I and II. In these early
stages of AKI, preventive measures to avoid progression to a more severe stage
are of utmost importance and these must also include metabolic/nutritional fac-
tors, such as electrolyte balance, avoidance of hyperglycemia, and prevention of
malnutrition.
Patients with AKI- RILFE Stage F/AKIN Stage III. In this more advanced stage of
AKI, RRT is usually employed early in order to minimize the systemic consequences
Table 3. Nutrient requirements in patient with renal failure
Energy intake 2030 (max. 35) kcal/kg/day
Glucose 35 g/kg/day
Lipids 0.81.2 (max. 1.5) g/kg/day
Amino acids/protein
Conservative therapy 0.81.2 g/kg/day
+ RRT 1.31.5 g/kg/day
+ Hypercatabolism max. 1.7 g/kg/day
Vitamins (combination products containing RDA)
Water- soluble 2 RDA/day
(caution: vitamin C <250 mg/day)
Lipid- soluble 1 2 RDA/day
(higher for vitamin D?)
Trace elements (combination products proving RDA)
1 RDA/day
(higher for selenium?)
Electrolytes: requirements must be assessed
individually (caution: refeeding hypophosphatemia
and/or hypokalemia)
Please note: Requirements differ between individual patients and may vary considerably during the
course of disease.
Renal Failure Patient 133
of renal dysfunction, to maintain volume and electrolyte balances, and support
hemodynamic and respiratory management. In this stage of AKI, the metabolic con-
sequences of renal dysfunction plus the effects of RRT have to be considered.
Enteral Nutrition (Tube Feeding)
Enteral nutrition is the primary type of nutritional support for all critically ill patients
as well as for patients with renal failure. Even small amounts of luminally provided diets
can help to support intestinal defense functions and reduce infectious complications.
Moreover, enteral nutrition might exert specific advantages in AKI. In experimen-
tal AKI, enteral nutrition can augment renal plasma flow and improve renal function
[21]. Enteral nutrition was a factor associated with an improved prognosis in criti-
cally ill patients with AKI [2].
Nevertheless, gastrointestinal motility is impaired in many patients with renal failure
and as it is frequently not possible to meet requirements by the enteral route alone, paren-
teral nutrition (at least supplemental and/or temporarily) may become necessary [11].
Unfortunately, few systematic studies on enteral nutrition have been conducted
in patients with AKI thus far. Nutritional effects, feasibility, and tolerance of enteral
nutrition were assessed in 182 patients with AKI [22]. Side effects of enteral nutrient
supply were higher and the amount of nutrient provided in patients with AKI was
lower, but in general enteral nutrition was well tolerated, safe, and effective.
Worldwide, most groups use standard diets in patients with renal failure as in other
(critically ill) patients. It should be noted that in acutely ill patients on RRT, hyper-
kalemia or hyperphosphatemia rarely are clinically relevant problems; therefore, the use
of electrolyte- restricted diets is usually not necessary. Enteral diets contain the RDA of
micronutrients for healthy subjects only and care should be taken that water- soluble vita-
mins, vitamin D, and potentially selenium and/or zinc are adequately supplemented.
Whether diets with the addition of various immunomodulating substrates (immu-
nonutrition) such as fish oil, antioxidants, nucleotides, or glutamine have advantages
in patients with renal dysfunction remains to be demonstrated.
Parenteral Nutrition
In the critically ill patient with renal dysfunction, it is frequently impossible to cover
nutrient requirements exclusively by the enteral route alone and supplementary or
even total parenteral nutrition may become necessary. Parenteral and enteral nutri-
tion should not be viewed as conflicting, but rather as complementary types of nutri-
tion support, a combination which enables an optimal nutrient provision in many
critically ill patients with renal failure.
134 Druml
1 Druml W: Acute renal failure is not a cute renal
failure! Intensive Care Med 2004;30:1886 1890.
2 Metnitz PG, Krenn CG, Steltzer H, et al: Effect of
acute renal failure requiring renal replacement ther-
apy on outcome in critically ill patients. Crit Care
Med 2002;30:2051 2058.
3 Druml W: Metabolic aspects of continuous renal
replacement therapies. Kidney Int Suppl 1999;72:
S56 S61.
4 Druml W: Nutritional management of acute renal
failure. J Ren Nutr 2005;15:63 70.
5 Schneeweiss B, Graninger W, Stockenhuber F, et al:
Energy metabolism in acute and chronic renal fail-
ure. Am J Clin Nutr 1990;52:596 601.
The use of total nutritional admixtures (all- in- one solutions) has become standard
worldwide. These solutions are either standard products provided by the pharma-
ceutical industry (as multichamber bags) or custom- made by the hospital pharmacy
or compounding companies. Usually, these multichamber bags are basic solutions
containing the three macronutrients (glucose, amino acids, and a lipid emulsion), in
part also variable amounts of electrolytes. Water and lipid- soluble vitamins, trace ele-
ments, and electrolytes have to be added as required before use.
Considering recent evidence, parenteral nutrition should not be started before 4 days
[23]. In patients with renal failure, however, pre- existing malnutrition and continued
nutrient losses during RRT can make it advisable to start parenteral nutrition earlier.
To ensure maximal nutrient utilization and avoid metabolic derangements, the
infusion should be started at a low rate (providing about 25% of requirements) and
gradually increased over several days. The nutrition solution should be infused
continuously over 24 h to ensure optimal substrate utilization and to avoid marked
changes in substrate concentrations in a state of impaired utilization in the presence
of renal dysfunction.
Complications and Monitoring
Technical problems and infectious complications originating from central venous
catheters or enteral feeding tubes, gastrointestinal side effects of enteral nutrition,
and metabolic complications during nutrition support are similar in patients with
renal failure and in nonuremic subjects.
However, both metabolic and gastrointestinal complications occur more fre-
quently and are far more pronounced in the presence of renal dysfunction because
the utilization of various nutrients is impaired and the tolerance to electrolytes and
volume is limited. Moreover, gastrointestinal motility is impaired. Because of this
high risk and frequency of metabolic complications, nutritional therapy in this spe-
cific patient population requires a tighter schedule of monitoring compared to other
patient groups. By gradually increasing the infusion rate and avoiding any infusion
above requirements, many side effects can be minimized.
References
Renal Failure Patient 135
6 Fiaccadori E, Maggiore U, Rotelli C, et al: Effects of
different energy intakes on nitrogen balance in
patients with acute renal failure: a pilot study.
Nephrol Dial Transplant 2005;20:1976 1980.
7 Basi S, Pupim LB, Simmons EM, et al: Insulin
resistance in critically ill patients with acute renal
failure. Am J Physiol Renal Physiol 2005;289:
F259 F264.
8 Schetz M, Vanhorebeek I, Wouters PJ, Wilmer A,
Van den Berghe G: Tight blood glucose control is
renoprotective in critically ill patients. J Am Soc
Nephrol 2008;19:571 578.
9 KDIGO Clinical Practice Guideline for Acute
Kidney Injury. Kidney Int Suppl 2012;2:1 138.
10 Druml W, Fischer M, Sertl S, Schneeweiss B, Lenz
K, Widhalm K: Fat elimination in acute renal fail-
ure: long- chain vs medium- chain triglycerides. Am
J Clin Nutr 1992;55:468 472.
11 Druml W, Mitch WE: Enteral nutrition in renal dis-
ease; in Rolandelli RH, Bankhead R, Boullata JI,
Compher CW (eds): Clinical Nutrition: Enteral and
Tube Feeding, ed 4. Philadelphia, WB Saunders,
2005, pp 471 485.
12 Fiaccadori E, Cremaschi E, Regolisti G: Nutritional
assessment and delivery in renal replacement ther-
apy patients. Semin Dial 2011;24:169 175.
13 Druml W: Protein metabolism in acute renal failure.
Miner Electrolyte Metab 1998;24:47 54.
14 Cano NJ, Aparicio M, Brunori G, et al: ESPEN
Guidelines on Parenteral Nutrition: adult renal fail-
ure. Clin Nutr 2009;28:401 414.
15 Scheinkestel CD, Kar L, Marshall K, et al: Prospective
randomized trial to assess caloric and protein needs
of critically ill, anuric, ventilated patients requiring
continuous renal replacement therapy. Nutrition
2003;19:909 916.
16 Druml W, Schwarzenhofer M, Apsner R, Horl WH:
Fat- soluble vitamins in patients with acute renal
failure. Miner Electrolyte Metab 1998;24:220 226.
17 Berger MM, Shenkin A, Revelly JP, et al: Copper,
selenium, zinc, and thiamine balances during con-
tinuous venovenous hemodiafiltration in critically
ill patients. Am J Clin Nutr 2004;80:410 416.
18 Metnitz GH, Fischer M, Bartens C, Steltzer H, Lang
T, Druml W: Impact of acute renal failure on anti-
oxidant status in multiple organ failure. Acta
Anaesthesiol Scand 2000;44:236 240.
19 Fortin MC, Amyot SL, Geadah D, Leblanc M: Serum
concentrations and clearances of folic acid and
pyridoxal- 5- phosphate during venovenous continu-
ous renal replacement therapy. Intensive Care Med
1999;25:594 598.
20 Demirjian S, Teo BW, Guzman JA, et al:
Hypophosphatemia during continuous hemodialy-
sis is associated with prolonged respiratory failure
in patients with acute kidney injury. Nephrol Dial
Transplant 2011;26:3508 3514.
21 Mouser JF, Hak EB, Kuhl DA, Dickerson RN, Gaber
LW, Hak LJ: Recovery from ischemic acute
renal failure is improved with enteral compared
with parenteral nutrition. Crit Care Med 1997;25:
1748 1754.
22 Fiaccadori E, Maggiore U, Giacosa R, et al: Enteral
nutrition in patients with acute renal failure. Kidney
Int 2004;65:999 1008.
23 Casaer MP, Mesotten D, Hermans G, et al: Early
versus late parenteral nutrition in critically ill adults.
N Engl J Med 2011;365:506 517.
Wilfred Druml, MD
Klinik fr Innere Medizin III, Abteilung fr Nephrologie
Whringer Grtel 18 20
AT 1090 Vienna (Austria)
Tel. +43 1 40400 4503, E- Mail wilfred.druml@meduniwien.ac.at
Organ- Targeted Nutrition
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 136143
n- 3 Fatty Acids and - Linolenic Acid
Supplementation in the Nutritional Support
of Ventilated Patients with Acute Lung Injury
or Acute Respiratory Distress Syndrome
Shaul Lev Pierre Singer
Department of Intensive Care, Beilinson Hospital, Rabin Medical Center, in affiliation with the Sackler
School of Medicine, Tel Aviv University, Petah Tikva, Israel
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are among the most frequent
etiologies for admission to the intensive care unit. These patients are at a high risk of malnutrition
due to hypercatabolism caused by inflammation, drugs, and de- conditioning. Nutrition should sup-
port minimizing the loss of lean body mass and accurately meet energy demands. Additional use of
omega- 3 fatty acid, - linolenic acid, and antioxidant- enriched diets has been suggested in recent
years as a tool to improve outcome in ALI/ARDS patients. More recent findings have taught us that
too much of these supplements are detrimental and that the bolus administration may not be as
efficient as continuous administration. Copyright 2013 S. Karger AG, Basel
Many patients on mechanical ventilation due to respiratory failure cannot be fed
orally. The risk of becoming malnourished is also increased by the fact that many
of these patients are already at risk for malnutrition before being ventilated due to
underling diseases. Many observational studies have found that malnutrition is asso-
ciated with poor outcomes in critically ill, mechanically ventilated patients [1].
In patients with respiratory failure due to acute lung injury (ALI) or acute respira-
tory distress syndrome (ARDS), the risk of malnutrition is even higher due to the long
duration of mechanical ventilation. While common practice is to provide early arti-
ficial nutrition starting with enteral nutrition targeted gradually to full caloric needs,
the best timing, formulation, and amount of enteral nutrition remain unknown. Some
recent data even suggest that hypocaloric feeding may be of benefit in some popula-
tions resulting in shorter duration of mechanical ventilation and improved clinical
outcomes [2].
n- 3 Fatty Acids and - Linolenic Acid Supplementation 137
Nutrition in Mechanically Ventilated Patients due to Acute Lung Injury/Acute
Respiratory Distress Syndrome
ALI/ARDS are characterized by inflammation and hyperpermeability. Release of
inflammatory mediators results in lung inflammation, edema, and diffuse alveolar
damage [3, 4]. The sudden onset of diffuse lung injury characterized by severe
hypoxemia (Pao
2
:Fio
2
ratio of <200 mm Hg) and generalized pulmonary infiltrates
in the absence of overt cardiac failure was first described as ARDS 40 years ago [4].
The cyclooxygenase complex derivatives are mediators of these processes. The type
of eicosanoids liberated during inflammation determines its inflammatory activ-
ity and is dependent on the membrane composition of omega- 6 fatty acids and
omega- 3 fatty acids. It is now widely believed that manipulation of n- 3/n- 6 fatty
acid supply can modify the cell membrane structure and consequently its func-
tion [5]. By changing membrane composition, these molecules affect membrane
fluidity, cell signaling processes, gene expression, and lipid and peptide mediators.
The omega- 6 fatty acid arachidonate yields highly inflammatory prostaglandins
and leukotrienes, whereas the omega- 3 fatty acids such as docosahexaenoic acid
(DHA) and eicosapentaenoic acid (EPA) favor production of less active and poten-
tially anti- inflammatory prostaglandins and leukotrienes. EPA and DHA are also
substrates for production of biologically potent lipid mediators called resolvins
and protectins, which are anti- inflammatory and inflammation resolving. The
anti- inflammatory effects of marine n- 3 fatty acids suggest that they may be use-
ful as therapeutic agents in disorders with an inflammatory component such as in
ALI/ARDS [6].
Animal Studies
Mayer et al. [7] examined the effect of n- 3 versus n- 6 fatty acids in a murine model
of ALI comparing transgenic fat- 1 to wild- type mice, avoiding possible confounding
effects of enteral or parenteral nutrition (exogenous supply of lipids may modulate
the infammatory response via the neuroendocrine axis, the vagus nerve, and acetyl-
choline receptors on leukocytes).
In this study, fat- 1 mice developed a less severe form of lung injury compared with
the wild- type animals after lipopolysaccharide instillation. Fat- 1 mice produced less
infammatory mediators, decreased neutrophil invasion, and reduced protein infux
in the alveolar space, together with improved lung compliance. The fat- 1 mice also
returned faster to normal body temperature, and exhibited a reduced loss of activity
compared with wild- type animals.
Supinski et al. [8] found in a rat model that endotoxin- induced reductions in
diaphragm- specific force generation can be partially prevented by administration of
EPA. The EPA ability to preserve diaphragm strength following endotoxin admin-
istration is probably mediated through the inhibition of diaphragmatic calpain I
activation.
138 Lev Singer
Peoples and McLennan [9] found the skeletal muscles of rats fed fsh oil to be more
resistant to fatigue during continuous muscle twitch contractions and recovered con-
tractile force better between repeat bouts. Surprisingly, it was achieved with reduced
skeletal muscle O
2
consumption both during contraction bouts and during recov-
ery. These changes in muscle function were associated with the incorporation of n- 3
PUFA into skeletal muscle membranes [9].
Patients with Acute Lung Injury/Acute Respiratory Distress Syndrome Receiving
Supplementation
Treatment of patients with ALI/ARDS usually includes nutritional support with lip-
ids. Historically, it was believed that carbohydrates should be avoided in ventilated
patients because of concerns regarding hyperglycemia and increased production of
carbon dioxide. This concept led to the manufacture of commercial enteral formula-
tion containing high- fat (predominately n- 6 and omega- 9 fatty acids) which could
potentially be metabolized into inflammatory mediators. Consequently, ALI/ARDS
patients were usually exposed to a relatively large amount of n- 6 fatty acids, which
appears to be undesirable in ARDS patients. Recently, patients with ALI/ARDS were
found to have very low n- 3 levels compared to normal individuals, suggesting a
potential role for n- 3 dietary supplementation in these patients [10]. Moreover, the
preclinical data reported previously supported the concept that EPA and DHA may
be beneficial in ALI/ARDS by reducing inflammation through reduced neutrophil
leukotriene synthesis and increased stimulation of E
1
.

Clinical data regarding specific n- 3 formulations in ALI/ARDS patients come
from six randomized controlled studies (table 1). The first three studies [11 13] dem-
onstrated an association between the administration of an enteral formula enriched
in n- 3 fatty acids, - linoleic acid (GLA), and antioxidants, and improved clinical out-
come as compared with high- fat formulas. These studies used the same study and
control formulas.
Gadek et al. [11] performed a prospective, multicenter, double- blind, randomized
controlled trial in 146 adult ARDS patients to assess if these bench findings apply to
bedside as well. Patients were randomly allocated to receive one of two commercially
available enteral nutrition formulas with similar caloric and protein content: a high-
fat, low- carbohydrate product or one enriched in fish oil, borage oil (rich in GLA),
and antioxidants (vitamins C and E, - carotene, and taurine). In this study, patients
receiving the n- 3 PUFA- rich formula displayed better oxygenation, shorter require-
ment for mechanical ventilation, shorter length of stay in ICU, and less incidence
of new organ failure. In the pulmonary assessment, total cell and neutrophil counts
recovered from the bronchoalveolar lavage showed a significant drop at study day
4 when the count was adjusted for volume of recovered alveolar fluid. Patients with
EPA and GLA had more (4.9 days) ventilator- free days of support. More ICU- free
days and even the hospital stay were shortened by 5.2 days. However, no difference in
mortality was observed.
n- 3 Fatty Acids and - Linolenic Acid Supplementation 139
Our group performed a randomized trial in 100 artificially ARDS or ALI venti-
lated patients [12]. The fish oil group showed an improvement in lung compliance
and LOV. There were no significant differences in the length of ICU/hospital stay and
mortality between the two groups.
Pontes- Arruda et al. [13] performed a double- blind study in which 165 patients
with severe sepsis or septic shock and a Pao
2
:Fio
2
ratio of less than 200 mm Hg
were assessed regarding clinical outcomes and laboratory markers. Fish oil- based
therapy had an impressive impact on the clinical outcome of the mortality rate,
which was 32.7 versus 52.1% in the control group. New organ dysfunction was also
reduced in the intervention group. Although ALI/ARDS per se were not inclu-
sion criteria in this trial, improvement in oxygenation and independence from
mechanical ventilation were more readily achieved in patients receiving fish oil-
based treatment. This study demonstrated a powerful protective effect for fish oil-
based nutrition in severely septic ill patients. A meta- analysis done on these three
trials [14] showed a significant reduction in the risk of mortality as well as relevant
improvements in oxygenation and clinical outcomes of ventilated patients with
ALI/ARDS.
Nevertheless, other studies addressed the same question in patients with ALI
or ARDS with mixed results. In a recent multicenter study [15], the study formula
was compared to a formula enriched in carbohydrate but less in lipids (table 1),
Table 1. Clinical and nutritional characteristics of the patients included in six recent studies. Severity score is
expressed by APACHE II or APACHE III (Rice study). Lipid administration is much higher in the Rice study group and
much lower in the Grau control group. Protein content is much lower in the Rice study group. Four studies used
enteral continuous administration, while the Stapleton and Rice studies used bolus administration of a much
higher dose of EPA and GLA. Length of ventilation and length of ICU stay are expressed in ventilation and ICU- free
days
Gadek
et al. [11]
Study Ctrl
Singer
[12]
Study Ctrl
Pontes- Arruda
[13]
Study Ctrl
Grau
et al. [15]
Study Ctrl
Stapleton
et al. [16]
Study Ctrl
Rice [17]
Study Ctrl
APACHE II 23 23 23 21 19 19 94 92
Lipids, g/l 92.1 93.7 93.7 92.1 92.1 93.7 92.1 33.4 ? 170 88
Protein, g/l
EPA, g/l
GLA, g/l
Cont./Bolus
62.6 62.5
4.3
4.3
C
62.6 62.5
5.4
4.3
C
62.6 62.5
4.9
4.3
C
62.6 66.6
5.4
4.3
C
?
9.7
10
B
13.5 80
28.5
24.7
B
Oxygenation
Vent.- free day
ICU- free day
Improved
17.6
12.7
16 11
Improved
15 10.4
13.3 9.6
Improved
11.4 3.8
8.8 2.6
Unchanged
18 19
12 10
Unchanged
14 13
12 11
Unchanged
14.0 17.2
14.0 16.7
Mortality, % 12 19 37 35 33 52 18 16 22 20 27 16
140 Lev Singer
and was less concentrated (1 kcal/ml vs. 1.5 kcal/ml in the study formula). The
results did not support the hypothesis that a diet enriched with GLA, EPA, and
antioxidants can decrease the incidence of novel organ failures (the EPA- GLA diet
group showed a trend towards a decreased SOFA score, but it was not signifcant).
In this study no improvement in the gas exchange measured by the Pao
2
/Fio
2
ratio
was measured in the n- 3 group. Liver function tests, glycemia, cholesterol, and
triglycerides were similar in both groups. There was a similar incidence of nosoco-
mial infections. The control group stayed significantly longer in the ICU than the
EPA- GLA diet group.
Stapleton et al. [16] performed a phase II randomized controlled trial in ventilated
adult patients with ALI. The subjects were randomized to receive enteral fish oil
(9.75 g EPA and 6.75 g DHA daily) or saline placebo for up to 14 days. The primary
endpoint was bronchoalveolar lavage fluid IL- 8 levels. Enteral fish oil administra-
tion was associated with increased serum EPA concentration. However, there was no
significant difference in the change in bronchoalveolar lavage fluid IL- 8 from base-
line to day 4 or day 8 between treatment arms. There were no appreciable improve-
ments in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil
group compared with the control group. Similarly, organ failure score, ventilator-
free days, intensive care unit- free days, and 60- day mortality did not differ between
the groups.
In the most recent study, the OMEGA trial [17], the authors used a different
approach of twice- daily bolus administration of n- 3 fatty acids instead of continu-
ous enteral infusions to deliver the supplements. In contrast to the previous studies
in this study, enteral supplementation of n- 3 fatty acids, GLA, and antioxidants did
not improve the rate of nosocomial- infections, nonpulmonary organ function, lung
physiology, or clinical outcomes in patients with ALI. Furthermore, the study was
stopped because of futility despite an eightfold increase in plasma EPA levels. Also
the use of the n- 3 supplement resulted in more days with diarrhea.
The interpretation of the OMEGA trial is difficult since reduced levels of IL- 8 and
leukotriene B
4
in bronchoalveolar lavage fluid have been observed in patients with
ALI treated with n- 3 fatty acids and correlated with improvements in pulmonary
physiology. In the OMEGA trial, these biological effects were not documented despite
a significant increase in serum plasma n- 3, implying lack of biological effect regarding
immunomodulation. Another difference between the OMEGA trial and the previous
studies is the composition of the control supplement which contained high- fat formu-
lation instead of protein and carbohydrates (table 1). Since most of the studies have
been conducted in different populations and with different nutritional regimens, table
1 underlines the variations between the studies and could be of value to weigh the uti-
lization of supplemental n- 3 fatty acids and GLA in ARDS/ALI patients.
The recommendations issued form large scientific societies dated from 2006 and
2009 are only based on the research published at the time of publication and are sum-
marized below.
n- 3 Fatty Acids and - Linolenic Acid Supplementation 141
Recommendations/Guidelines
The ESPEN guidelines [18] published in 2006 give a grade B recommendation to the
use of omega- 3 fatty acids in fish oil in patients with ALI/ARDS (Patients with ARDS
should receive EN enriched with x- 3 fatty acids and antioxidants (B)).
This recommendation was not evaluated in the guidelines for parenteral nutrition
regarding ALI/ARDS patients, although the authors stated that Addition of EPA and
DHA to lipid emulsions has demonstrable effects on cell membranes and inflamma-
tory processes [18].
The ASPEN (American Society of Parenteral and Enteral Nutrition) guidelines sug-
gested in 2002 that for patients with early ARDS, products containing omega- 3 fatty
acids may be beneficial, based on the results of the study by Gadek et al. [11], the only
study performed at the time. In 2009 the guidelines stated that patients with ARDS
and ALI should receive an enteral formulation characterized by an anti- inflammatory
lipid profile enriched in EPA, GLA, and antioxidants [19]. The recommendation was
based on the three positive trials published at that time.
According to one level 1 study and two level 2 studies, the Canadian guidelines
recommended the use of an enteral formula with fish oils, borage oils, and antioxi-
dants in ARDS patients [20].
Intravenous Fish Oil Administration
Recently, three studies introduced the use of intravenous fish oil in various critical con-
ditions. Barbosa et al. [21] included 25 patients with SIRS or sepsis and randomized
them into two groups receiving an IV lipid emulsion enriched (or not) in fish oil. Fish
oil increased EPA in plasma phosphorylcholine, IL- 6 concentration was decreased sig-
nificantly, and at day 6 the Pao
2
/Fio
2
ratio was significantly higher in the fish oil group
(p < 0.05). Days of ventilation, length of ICU stay, and mortality were not different between
the two groups. Gupta et al. [22] examined the impact of parenteral omega- 3 fatty acids
alone on ventilatory parameters and clinical outcome of ARDS patients who were oth-
erwise fed enterally. Supplementation of enteral nutrition with parenteral fish oil for 14
days did not affect any ventilatory parameters or measures of clinical outcome in these
patients. Finally, Sabater et al. [10] studied 16 consecutive patients with ARDS in the first
48 h after admission. They found a favorable lipid mediator synthesis profile in patients
treated with fish oil- enriched lipid emulsion, but not in patients treated with LCT.
Conclusions
ALI/ARDS patients are at high risk of malnutrition. Meticulous nutritional evalua-
tion is essential in order to minimize loss of lean mass and accurately meet energy
142 Lev Singer
1 Oltermann MH: Nutrition support in the acutely
ventilated patient. Respir Care Clin N Am 2006;12:
533545.
2 Rice TW, Mogan S, Hays MA, Bernard GR, Jensen
GL, Wheeler AP: Randomized trial of initial trophic
versus full- energy enteral nutrition in mechanical
ventilated patients with acute respiratory failure.
Crit Care Med 2011;39:967 974.
3 Armstrong L, Millar AB: Relative production of
tumour necrosis factor alpha and interleukin 10 in
adult respiratory distress syndrome. Thorax 1997;52:
442 446.
4 Leaver SK, Evans TW: Acute respiratory distress
syndrome. BMJ 2007;335:389394.
5 Senkal M, Geier B, Hannemann M, et al:
Supplementation of n- 3 fatty acids in parenteral
nutrition beneficially alters phospholipid fatty acid
pattern. JPEN J Parenter Enteral Nutr 2007;31:
1217.
6 Singer P, Shapiro H, Theilla M, Anbar R, Singer J,
Cohen J: Anti- inflammatory properties of omega- 3
fatty acids in critical illness: novel mechanisms and
an integrative perspective. Intensive Care Med 2008;
34:1580 1589.
7 Mayer K, Kiessling A, Ott J, et al: Acute lung injury
is reduced in fat- 1 mice endogenously synthesizing
n- 3 fatty acids. Am J Respir Crit Care Med 2009;179:
474 483.
8 Supinski GS, Ji X, Vanags J, Callahan LA:
Eicosapentaenoic acid preserves diaphragm force
generation following endotoxin administration.
Crit Care 2010;14:R35.
9 Peoples GE, McLennan PL: Dietary fish oil reduces
skeletal muscle oxygen consumption, provides
fatigue resistance and improves contractile recovery
in the rat in vivo hindlimb. Br J Nutr 2010;9:1 9.
10 Sabater J, Masclans JR, Sacanell J, Chacon P, Sabin P,
Planas M: Effects on hemodynamics and gas
exchange of omega- 3 fatty acid- enriched lipid emul-
sion in acute respiratory distress syndrome (ARDS):
a prospective, randomized, double- blind, parallel
group study. Lipids Health Dis 2008;7:39.
11 Gadek JE, DeMichele SJ, Karlstad MD, et al; Enteral
Nutrition in ARDS Study Group: Effect of enteral
feeding with eicosapentaenoic acid, gamma-
linolenic acid, and antioxidants in patients with
acute respiratory distress syndrome. Crit Care Med
1999;27:14091420.
12 Singer P, Theilla M, Fisher H, Gibstein L, Grozovski
E, Cohen J: Benefit of an enteral diet enriched with
eicosapentaenoic acid and gamma- linolenic acid in
ventilated patients with acute lung injury. Crit Care
Med 2006;34:1033 1038.
13 Pontes- Arruda A, Aragao AM, Albuquerque JD:
Effects of enteral feeding with eicosapentaenoic
acid, gamma- linolenic acid, and antioxidants in
mechanically ventilated patients with severe sepsis
and septic shock. Crit Care Med 2006;34:2325
2333.
14 Pontes- Arruda A, Demichele S, Seth A, Singer P:
The use of an inflammation- modulating diet in
patients with acute lung injury or acute respiratory
distress syndrome: a meta- analysis of outcome data.
J Parenter Enteral Nutr 2006;32:596 605.
15 Grau- Carmona T, et al: Effect of an enteral diet
enriched with eicosapentaenoic acid, gamma-
linolenic acid and anti- oxidants on the outcome of
mechanically ventilated, critically ill, septic patients.
Clin Nutr 2011;30:578 584.
16 Stapleton RD, Martin TR, Weiss NS, et al: A phase II
randomized placebo- controlled trial of omega- 3
fatty acids for the treatment of acute lung injury.
Crit Care Med 2011;39:1655 1662.
demands. Novel biochemical and clinical results suggest that the change of the n- 3/n-
6 ratio by fatty acid supply could be an important factor affecting the alveolar cytokine
release. These experimental data support the current recommendations regarding
ALI/ARDS patients that encourage the use of formulas enriched with omega- 3 fatty
acids in order to improve oxygenation and even clinical outcomes. Recent findings
do not suggest providing megadoses of n- 3 fatty acids in bolus, but encourage con-
ducting more studies comparing the continuous enteral administration of n- 3 fatty
acids in ALI and ARDS patients to define the precise timing and indications for this
administration.
References
n- 3 Fatty Acids and - Linolenic Acid Supplementation 143
17 Rice TW, Wheeler AP, Thompson BT, et al: Enteral
omega- 3 fatty acid, gamma- linolenic acid, and anti-
oxidant supplementation in acute lung injury.
JAMA 2011;306:1574 1581.
18 Kreymann KG, Berger MM, Deutz NDP, et al:
ESPEN Guidelines on Enteral Nutrition: intensive
care. Clin Nutr 2006;25:210 223.
19 McClave SA, Martindale RG, Vanek VW, 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 for Parenteral and
Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter
Enteral Nutr 2009;33;277 316.
20 Heyland DK, Dhaliwal R, Drover JW, Gramlich L,
Dodek P, Canadian 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;27:355 373.
21 Barbosa VL, Miles EA, Calhau C, Lafuente E, Calder
P: Effects of a fish oil containing lipid emulsion on
plasma phospholipid fatty acids, inflammatory
markers, and clinical outcomes in septic patients: a
randomized, controlled clinical trial. Crit Care
2010;14:R5.
22 Gupta A, Govil D, Bhatnagar S, et al: Efficacy and
safety of parenteral omega 3 fatty acids in ventilated
patients with acute lung injury. Indian J Crit Care
Med 2011;15:108 113.
Pierre Singer, MD
Critical Care Medicine, Institute for Nutrition Research
Rabin Medical Center, Beilinson Hospital
IL 49100 Petah Tikva (Israel)
Tel. + 972 3 9376521, E- Mail psinger@clalit.org.il
Organ- Targeted Nutrition
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 144153
Obesity
David C. Frankenfield
Department of Clinical Nutrition and Department of Nursing, Penn State Milton S. Hershey Medical Center,
Hershey, Pa., USA
Abstract
Obesity has become common in critically ill patients as it is in the population at large. Despite large
fuel stores, obese patients can become rapidly malnourished and are subject to the same inflam-
matory and catabolic responses as their nonobese counterparts. The concepts of early enteral
nutrition are therefore equally applicable to the obese patient as to the nonobese patient.
Monitoring of nutrition support likewise is the same. The main differences in obese versus non-
obese patients is that nutrition assessment is somewhat more uncertain, and that hypocaloric high-
protein feeding is more often recommended in the obese. The rationale for hypocaloric feeding in
obese patients is multipart: (1) energy balance is not necessary to achieve nitrogen balance, (2)
energy expenditure is difficult to predict in obese patients and is likely to lead to overfeeding, (3)
overfeeding is especially detrimental to the obese patient, and (4) positive outcomes have been
observed with hypocaloric high- protein feeding. That nitrogen balance can be achieved without
energy balance has been demonstrated in several studies. However, the likelihood of overestimat-
ing resting metabolic rate in the obese may be overstated, and the evidence that hypocaloric feed-
ing improves outcome is limited. It is therefore still an open question as to whether hypocaloric
high- protein feeding should be standard practice in obese critically ill patients.
Copyright 2013 S. Karger AG, Basel
Obesity is common amongst patients admitted to critical units [1] and presents
a challenge to their nutritional assessment and care. This being said, there are
many aspects of nutrition care that are the same for obese and nonobese patients,
including timing and route of feeding, monitoring techniques, and the use of spe-
cialized nutrients [2]. These will not be discussed in this chapter. Focus will be
on the differences in care between obese and nonobese patients. Specifically the
differences in assessment and the use of hypocaloric high- protein feeding will be
highlighted.
Obesity 145
Body Composition
The salient feature of obesity is accumulation of body fat. Less obviously, there is also
an increase in muscle mass [3, 4] attributable to a training effect of carrying around
extra body weight. However, increased muscle mass is not universally the case. In
people who become so large that movement is restricted, in some older obese people,
and in people who develop chronic illness, sarcopenia can be a feature of obesity [4].
Organ mass is relatively unaffected by obesity. Extracellular mass usually increases
[3]. Because each of these tissue compartments has different metabolic rates, obe-
sity can change the relationship between body size and metabolic rate, and therefore
change the accuracy of metabolic assessments.
Most calculations of nutrient needs are weight- based and it is thought that use of
actual body weight in an obese patient will cause overestimation of needs. Various
adjustments to body weight are used to adapt nutrient calculations to the obese. The
modifications are designed generally to approximate fat- free mass [5]. The procedure
is to partition excess body weight into fat and nonfat weight. To determine excess
weight, the first step is to calculate ideal body weight:
1 Men: 48 kg for the frst 152 cm of height plus 1.07 kg for each additional cm of
height
2 Women: 45 kg for the frst 152 cm of height plus 0.89 kg for each additional cm of
height.
Excess body weight is then calculated as body weight minus ideal body weight.
Finally, adjusted body weight is calculated as some percentage of the excess body
weight added to the ideal body weight:
1 Average weight: (weight ideal weight) 0.50 + ideal body weight
2 Metabolically active weight: (weight ideal weight) 0.25 + ideal body weight.
Energy Expenditure
Resting metabolic rate (RMR) is proportional to body weight, but in a nonlinear fash-
ion (fig. 1) [6]. In data from Frankenfield et al. [7, 8], in healthy people with BMI
30 40, body weight was 40% higher than in people with BMI <30, but RMR was only
23% higher (table 1). In people with BMI >40, the body weight was 120% higher, but
RMR was only higher by 60%. Despite this, use of actual body weight in the linear
equation by Mifflin [9] adequately indexes RMR in healthy obese people (table 1) and
accurately predicts the true RMR about 75% of the time [8, 10]. None of the common
body masses by themselves (weight, ideal weight, metabolically active weight) suc-
cessfully index RMR.
In the critically ill, RMR increases, but the increase is smaller in patients with BMI
>40 (table 1). Whereas the increase in patients with BMI <30 and 30 40 is 25%, the
increase is only 14% in patients with BMI >40. One possible reason for this is that
146 Frankenfield
most of the critically ill patients were sedated and all were mechanically ventilated,
so the increased work of breathing that is usually present in the severely obese [11] is
absent in this group.
Protein
Protein needs are usually elevated in critically ill patients [2]. Little standardization
exists for calculation of protein requirements. Most often protein is calculated in g/
kg of body mass, but the amount ranges from 1.2 to >2.0 g/kg and the body mass
value is sometimes ideal body weight and sometimes metabolically active weight.
The ASPEN/SCCM clinical guideline recommends the use of ideal body weight and
increases the protein load per kg as obesity increases, independent of illness sever-
ity [2]. This is an implicit acknowledgement of a weakness of ideal body weight for
calculation of protein needs. Ideal body weight is a function of height and therefore
does not change with increasing body weight. As obesity worsens, there is an increase
in fat- free mass [4, 12], but not in ideal body weight. Thus, to keep the protein intake
proportional to body protein mass, the amount of protein per kg of ideal body weight
must increase. Metabolically active body weight does increase with increasing body
Equation method
Allometric (Livingston)
Linear (Frankenfeld)
C
a
l
c
u
l
a
t
e
d

R
M
R

(
k
c
a
l
/
d
a
y
)
Body weight (kg)
0 25 50 75 100 125 150 175 200
500
750
1,000
1,250
1,500
1,750
2,000
2,250
2,500
2,750
3,000
Linear: RMR = 647 + wt (11)
Allometric: RMR = 202 wt
0.4722
BMI >45
Fig. 1. Relationship between body weight and RMR. Although the relationship is allometric, the
deviation from linear is slight and does not become important until body weight becomes very large
or very small. This may explain why linear equations for predicting RMR are successful despite the
presence of an allometric relationship. The final, definite version of the figure has been published in
[6]. Published with kind permission of SAGE Publications.
Obesity 147
Table 1. Differences and percent changes in body size and metabolic rate in healthy and critically ill people grouped by
BMI
Variable Healthy Critically ill
BMI group mean SD percent of
nonobese group
BMI group mean SD percent of
nonobese group
Age, years 1 4016 NA 1 5721 NA
2 4113 NA 2 5717 NA
3 398 NA 3 5814 NA
Height, cm 1 17010 NA 1 1709 NA
2 17011 NA 2 17211 NA
3 16911 NA 3 17011 NA
Weight, kg 1 6912 1.00 1 7411 1.00
2 9917 1.42 2 10315 1.39
3 15243 2.19 3 14242 1.92
BMI 1 24.02.8 1.00 1 25.32.6 1.00
2 33.93.2 1.42 2 34.32.6 1.36
3 52.710.9 2.19 3 49.113.2 1.94
RMR, kcal/day 1 1471254 1.00 1 1824400 1.00
2 1801391 1.23 2 2202482 1.20
3 2386521 1.62 3 2361493 1.29
RMR, % Mifflin 1 1.010.08 1.00 1 1.250.17 1.00
2 1.030.13 1.02 2 1.260.16 1.01
3 1.040.09 1.03 3 1.140.16 0.91
RMR, kcal/wt 1 212 1.00 1 254 1.00
2 183 0.86 2 213 0.87
3 162 0.74 3 173 0.69
RMR, kcal/IBW 1 212 1.00 1 254 1.00
2 285 1.33 2 324 1.28
3 385 1.01 3 366 1.44
RMR, kcal/MAW 1 212 1.00 1 254 1.00
2 254 1.12 2 294 1.16
3 283 1.27 3 284 1.11
Healthy ambulatory volunteers (n = 134): 84 in group 1, 21 in group 2, 29 in group 3. Critically ill, mechanically ventilated
critical care patients (n = 201): 101 in group 1, 66 in group 2, 34 in group 3. BMI groups: 1 = BMI <30, 2 = 30- 40, 3 = BMI >40.
Mifflin = RMR predicted by the Mifflin St. Jeor equation; IBW = ideal body weight in kg; MAW = metabolically active weight
in kg.
148 Frankenfield
weight and therefore does not require an increase in the protein load per kg to keep
pace. The protein intake can then be adjusted for the degree of catabolism rather than
the degree of obesity. With all the uncertainty and conjecture involved with calcula-
tion of protein needs in the obese, the most important tool for protein assessment is
the nitrogen balance study, which allows protein intake to be adjusted to nitrogen
loss.
Hypocaloric Feeding
Hypocaloric high- protein feeding has received much attention as a feeding approach
in the obese patient to improve clinical outcome while minimizing possible com-
plications of overfeeding [2, 13, 14]. The ASPEN/SCCM clinical guideline endorses
the hypocaloric high- protein feeding approach. Since recommendations for the tim-
ing and route of feeding are the same for obese and nonobese critical care patients,
the decision to implement hypocaloric high- protein feeding is perhaps the primary
difference in the nutritional care of obese versus nonobese patients in the intensive
care unit. The rationale for hypocaloric high- protein feeding is that on one hand
nitrogen balance does not deteriorate during underfeeding of energy in stressed
patients [15 17], and on the other hand that RMR is more difficult to predict in obese
patients, that overfeeding is more likely, and that overfeeding increases the produc-
tion of carbon dioxide that obese patients cannot ventilate as efficiently as nonobese
patients [18]. Obese patients are therefore more prone to and more sensitive to the
effects of overfeeding. We will examine each part of this rationale.
Nitrogen Balance
Eucaloric feeding has been demonstrated at least three times to be unnecessary for
the achievement of nitrogen balance in critically ill patients [15 17], including the
obese. Muscle catabolism likewise has been shown to not increase with hypocaloric
feeding, although if no kilocalories are provided, the catabolic rate rises [19].
Ventilatory Function and Carbon Dioxide Load
Obesity is responsible for numerous mechanical and metabolic alterations in lung
function resulting in increased work of breathing and decreased ventilatory capacity
[17, 18]. Minimizing the impact of feeding on the requirement for oxygenation and
ventilation in obese people therefore is important to consider. Avoidance of over-
feeding is the primary way that nutrition support can minimize carbon dioxide pro-
duction. However, the effect may be small. Oxidation of fuel requires oxygen and
converts macronutrients to carbon dioxide regardless of the mix of fuels utilized.
Thus, there is a strong link between overall fuel demand, oxygen consumption, and
carbon dioxide production (Vco
2
). Reduced structural and functional robustness
of the respiratory system makes the obese patient susceptible to respiratory failure.
Obesity 149
Because of this propensity toward impaired carbon dioxide handling, minimizing
Vco
2
may be of benefit in the care of obese patients in the critical care unit, but com-
pared to the Vco
2
associated with overall energy demands, the added carbon diox-
ide related to feeding is minor, accounting for 13% of the total Vco
2
in overfeeding
conditions versus 8% in underfeeding or adequate feeding (fig. 2) [unpubl. analysis
of data from reference 7]. These percentages are the same in nonobese patients (14
and 8%). Despite the increase in Vco
2
associated with overfeeding, the overall Vco
2

was lower in the overfed obese patients (263 42 ml/min vs. 279 60 ml/min) and
neither the P
a
co
2
(39.2 6.3 vs. 38.2 6.3 torr) nor the ratio of minute ventilation to
Vco
2
(Ve
VCO2
; 44.0 10.6 vs. 46.6 10.7) were altered.
Accuracy of Metabolic Rate Assessment
Measurement of RMR with indirect calorimetry is the criterion method for deter-
mining energy demand. Due to cost factors, most institutions do not have indirect
calorimetry and therefore mathematical equations are routinely used to estimate
energy requirements. This reliance on equations is one of the rationales for hypoca-
loric feeding for the obese (i.e. that the equations are largely inaccurate and prone
to overestimation and since obese patients are sensitive to overfeeding, it is best to
Obese underfed
O
b
e
s
e

o
v
e
r
f
e
d
N
o
n
o
b
e
s
e

u
n
d
e
r
f
e
d
Nonobese overfed
RQ = 1.0
50
100
150
200
250
300
350
400
450
500
550
100 150 200 250 300 350 400 450 550 600 500
C
O
2

p
r
o
d
u
c
t
i
o
n

(
m
l
/
m
i
n
)
Oxygen consumption (ml/min)
Fig. 2. Carbon dioxide production as a function of oxygen consumption in nonobese and obese
critically ill patients. Regression line is VCO
2
= 12.3 + 0.760 VO
2
+ 0.863 total kcal intake/kg metaboli-
cally active weight (R
2
0.92). Closed circles are obese patients, open circles are nonobese patients.
Broken lines represent the differences in VCO
2
in obese underfed and overfed patients across the
range of VO
2
using the mean caloric intake to compute the VCO
2
from the regression. Solid lines show
the same relationship for nonobese overfed and underfed patients. Also shown is the line of identity
[where respiratory quotient (RQ) = 1.0].
150 Frankenfield
avoid overfeeding by systematically underfeeding energy while providing high pro-
tein intake). As a major factor in support of hypocaloric feeding, the assumption that
RMR equations fail in the obese needs to be examined.
Many RMR equations have been proposed, reflecting the near desperation clini-
cians feel to get the energy prescription correct when the criterion method of indi-
rect calorimetry is not available. Many of these equations have been recruited from
their original use of predicting RMR in healthy people and have proved to be invalid.
Therefore, only three equations will be highlighted in this text. These three are the
American College of Chest Physicians (ACCP) standard of 25 kcal/kg body weight
because it is widely applied [20], the Penn State equation because it uses fixed vari-
ables that relate to body size and dynamic variables that relate to the inflammatory
response [21, 22], and the Faisy equation which takes the same approach as the Penn
State equation but which was developed in Europe rather than the United States [23].
Both the Penn State and Faisy equations use actual body weight in their computation.
The ACCP standard is used in multiple ways in practice so it was computed three
ways here: using actual body weight, using ideal body weight, and using metabolically
active weight.
The data are compiled from Frankenfield et al. [21, 22]. Fifty- three older obese
patients were excluded from Frankenfield et al. [21] because significant prediction
error in this group prompted the development of a variation of the Penn State equa-
tion which was subsequently validated in Frankenfield [22]. The Penn State equa-
tion was the most accurate, followed by Faisy, and then ACCP using metabolically
active weight (table 2). The Penn State equation was more accurate in nonobese than
Table 2. Performance of metabolic rate equations in obese compared to nonobese critically ill patients
Equation BMI 20.029.9
n = 101
BMI 30.040.0
n = 66
BMI >40.0
n = 34
10%
1
>10%
2
>+10%
3
range
4
+10%
1
>10%
2
>+10%
3
range
4
+10%
1
>10%
2
>+10%
3
range
4
ACCP
wt
0.48 0.20 0.32 31 to 42 0.36 0.00 0.63 10 to 61 0.06 0.00 0.94 0 to 161
ACCP
MAW
0.38 0.58 0.04 31 to 18 0.59 0.38 0.03 32 to 17
ACCP
IBW
0.18 0.81 0.00 40 to 5 0.03 0.97 0.00 50 to 25
Faisy 0.51 0.08 0.41 20 to 44 0.68 0.09 0.23 27 to 30 0.62 0.06 0.32 17 to 29
Penn state 0.74 0.14 0.12 31 to 39 0.67 0.21 0.12 20 to 22 0.74 0.09 0.17 19 to 34
ACCP = American College of Chest Physicians standard (25 kcal/kg); wt = per kilogram body weight; MAW = per kilogram
metabolically active body weight; IBW = per kilogram ideal body weight.
1
Percentage of patients with calculated RMR within 10% of measured.
2
Percentage of patients with calculated RMR more than 10% lower than measured.
3
Percentage of patients with calculated RMR more than 10% greater than measured.
4
Most extreme underestimation and overestimation, as a percentage of measured.
Obesity 151
obese patients (74 vs. 69%). Faisy was more accurate in obese than nonobese patients
(66 vs. 52%), and the ACCP equation was accurately roughly half the time in both
patient groups (45% in obese patients, 48% in nonobese patients). The ACCP stan-
dard is inaccurate no matter which body weight is used in the calculation. However,
if avoidance of overestimation is the primary objective of the exercise, ACCP using
either metabolically active body weight or ideal body weight will accomplish the task.
The price for avoidance of overestimation is nearly universal underestimation of RMR
if ideal body weight is used. Use of metabolically active body weight offers the best
balance between avoiding overestimation without underpredicting the metabolic rate
of everybody and also reducing the range of individual errors. The Penn State equa-
tion overestimates RMR in 12% of moderate and 17% of severe obesity cases. The
issue becomes a trade- off. Is avoidance of overestimation worth widespread underes-
timation, or is the highest accuracy rate worth exposing some patients to overestima-
tion? Perhaps only outcome studies related to feeding level can answer this question.
Outcomes Related to Energy and Protein Balance
Dickerson published the only study finding a favorable outcome from hypocaloric
high- protein feeding in obesity [14] (there are a few other studies showing favorable
outcome in mixed obese and nonobese populations). This was a retrospective observa-
tional study of 40 critically ill trauma patients whose nutrition support was guided by
a nutrition support team. This team had the discretion to feed eucaloric or hypocaloric
regimens. The goal intake in the eucaloric group was 25 30 kcal/kg metabolically active
weight. The target intake for the hypocaloric regimen was <20 kcal/kg meta bolically
active body weight. Protein intake for both groups was targeted at 2.0 g/kg ideal body
weight. BMI was not statistically significantly different between the groups, but there
was a degree of difference (41.3 13.7 for the hypocaloric group vs. 36.0 12.4 for
the eucaloric group). Energy intake across 4 weeks of feeding was about 23 kcal/kg
metabolically active body weight in the eucaloric group and 15 kcal/kg metabolically
active body weight for the hypocaloric group. Length of stay in the intensive care unit
was significantly shorter in the hypocaloric group (18.6 vs. 28.5 days, p < 0.05) with a
trend toward fewer ventilator days (15.9 vs. 23.7, p < 0.09). Duration of antibiotic ther-
apy was significantly shorter in the hypocaloric group (16.6 vs. 27.4 days, p < 0.05).
All of the subjects in this study were trauma patients, so it is possible that the benefit
of hypocaloric feeding might not be generalizable to a more mixed critical care popu-
lation. Also, since the nutrition support team had discretion as to which regimen to
apply to which patient, it is possible that selection bias was present, though it is pre-
sumable that the selection bias would favor eucaloric feeding if hypocaloric feeding
was reserved for the larger and/or more severely ill patients.
More recent studies in critically ill patients have tended to find positive outcome
when energy and protein balance was more positive. Unlike the Dickerson study, in
the more recent studies examining outcome and intake of energy and protein, obese
patients were not the focus of the research, but they were likely included in the patient
152 Frankenfield
1 Lopez AD, Mathers CD, Ezzati M, Jamison DT,
Murray CJ: Global and regional burden of disease
and risk factors, 2001: systematic analysis of popu-
lation health data. Lancet 2006;367:1747 1757.
2 McClave SA, Martindale RG, Vanek VW, McCarthy
M, Roberts P, Taylor B, Ochoa JB, Napolitano L,
Cresci G: Guidelines for the Provision and
Assessment of Nutrition Support Therapy in the
Adult Critically Ill Patient. Society for Critical Care
Medicine, American Society for Parenteral and
Enteral Nutrition. JPEN J Parenter Enteral Nutr
2009;33:277 316.
3 Mller MJ, Bosy- Westphal A, Kutzner D, Heller M:
Metabolically active components of fat- free mass
and resting energy expenditure in humans: recent
lessons from imaging technologies. Obes Rev 2002;
3:113 122.
4 Gallagher D, DeLegge M: Body composition (sar-
copenia) in obese patients: implications for care in
the intensive care unit. JPEN J Parenter Enteral Nutr
2011;35:21S 28S.
5 Forbes GB, Welle SL: Lean body mass in obesity. Int
J Obes 1983;7:99 107.
cohort. For instance, Heidegger [24] reported on 275 patients with a mean BMI of
26.6 4.7. The 886 patients studied by Weijs et al. [25] had a mean BMI of about
25 6, and Singer et al. [26] studied 130 patients with a mean BMI of 28 6. Assuming
a normal distribution for the reported BMI, then anywhere from 15 to 35% of these
subject samples were obese. All three of these studies noted an outcome advantage
by meeting energy and protein targets. One large study of outcome related to energy
balance actually subgrouped their sample by BMI. Alberda et al. [27] conducted a
prospective observational study of 2,772 patients divided into three BMI categories.
Patients with BMI <25 and >35 derived benefit from increasing energy intake, but
there was no advantage in the BMI range of 25 35. Incidentally, this is roughly the
BMI range in which the obesity paradox operates (patients with BMI 30 40 seem not
to suffer the same morbidity and mortality as smaller and larger patients) and also the
mean BMI of the eucaloric group in Dickersons study was very close to being within
the 25 35 segment in which Alberda could find no advantage to reaching energy bal-
ance, while Dickersons hypocaloric group mean BMI was well within the cohort that
Alberda found to benefit from achieving energy balance (BMI >35).
Conclusion
Nutrition care of the obese critically ill patient is the same in most respects to care in
nonobese patients. The role of hypocaloric feeding may be the most salient difference
between the two. An often- stated reason for hypocaloric feeding is that prediction of
energy needs is inaccurate and leads to overfeeding. This may not be true if proper
equations are used. The evidence that hypocaloric feeding is beneficial is limited.
It therefore remains an open question whether hypocaloric high- protein feeding is
preferred in the obese. Other aspects of nutrition care do not differ from obese and
nonobese patients. Whenever possible, enteral nutrition should be started early in the
course of critical care, and should be carefully monitored.
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David C. Frankenfield, MS, RD
Department of Clinical Nutrition and Department of Nursing
Penn State Milton S. Hershey Medical Center
500 University Drive
Hershey, PA 17033 (USA)
Tel. +1 717 531 6042, E- Mail Dfrankenfield@hmc.psu.edu
Organ- Targeted Nutrition
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 154159
Nutritional Imbalances during
Extracorporeal Life Support
Ilya Kagan Pierre Singer
General Intensive Care Department and Institute for Nutrition Research, Rabin Medical Center,
Beilinson Hospital, Petah Tikva, Israel
Abstract
Extracorporeal life support has become an integral part of the technologies used in the intensive
care. Renal replacement therapy is used daily and extracorporeal membrane oxygenation (ECMO)
has become more popular in the recent years with the increasing prevalence of influenza- induced
severe respiratory failure. Many years ago, critically ill infants requiring ECMO were found to have the
highest rates of whole body protein breakdown ever recorded. However, most of the physicians are
not aware of the nutritional consequences of the use of new technologies. The aim of this chapter is
to describe the changes induced by artificial membranes and the required therapies to optimize
nutritional support. Copyright 2013 S. Karger AG, Basel
The quality and technology employed in extracorporeal therapies have improved
in terms of biocompatibility of the materials used. Protein oxidation was observed
together with cellulose acetate membranes and their switch to polysulfone membrane
has decreased inflammation and oxidative stress, too [1, 2]. This progress observed
in renal replacement therapy (RRT) can also improve the stress induced by extracor-
poreal membrane oxygenation (ECMO). This technique is not only increasing whole
body protein breakdown [3], but also inducing systemic inflammatory response syn-
drome, which can be associated with multiorgan failure and mortality [4]. A better
knowledge of the metabolic changes observed during these techniques may help pre-
vent some of the complications associated with membrane use.
Nutritional Requirements during Continuous Renal Replacement Therapy
Acute kidney injury (AKI) is one of the most common and severe complications in
the ICU, often associated with the failure of other organs. Sepsis is the leading etio-
logic factor of AKI [5, 6]. The prevalence of AKI in the critically ill is between 10
Nutritional Imbalances during Extracorporeal Life Support 155
and 30%, depending on definition, and 5 10% of the patients suffering from AKI
need RRT [6]. Intermittent hemodialysis and continuous renal replacement therapy
(CRRT), which is better tolerated by patients with cardiovascular instability, are the
most common modalities used for treatment of patients with AKI. There are sev-
eral hybrid techniques of intermittent hemodialysis and CRRT, such as continuous
venovenous hemofiltration or hemodiafiltration, extensive daily dialysis, slow low
efficient daily dialysis (SLEDD), and high- volume hemofiltration available for treat-
ment of AKI [5, 6]. During hemodialysis, based on diffusion, solutes cross the mem-
brane by concentration gradient between the dialysate fluid and the blood. However,
the basic principle of hemofiltration is convection, leading to the removal of small-
and middle- sized molecules [7], and ultrafiltration when plasma water is driven by
hydrostatic force across a semipermeable membrane [8].
Hypermetabolic state, fluid overload, protein- energy wasting, and inadequate
response are the main causes of the poor nutritional status of critically ill patients suf-
fering from AKI (see previous chapter [this vol., pp. 126135]). For patients under-
going hemodialysis or CRRT, losses of nutrients across a semipermeable membrane
due to nonselective solute shifts and supply of same nutrients via replacement fluids
could be additional factors inducing profound metabolic derangements [9, 10]. In
contrast to normal kidney that reabsorbs nutrients after glomerular filtration, sub-
stances such as amino acids, trace elements, and water- soluble vitamins are lost dur-
ing RRT. Moreover, continuous contact of a patients blood with foreign surfaces of
the membrane contributes by oxidative stress transforming lipids and proteins [11].
In this context, early nutritional assessment and adequate support may be a crucial
part in the management of critically ill patients treated by RRT for AKI.
Energy provision in ICU patients should be individual. Despite the fact that rest-
ing energy expenditure (REE) in AKI patients is not elevated, in critically ill patients
affected by coexisting conditions like sepsis or heat loss from extracorporeal blood
circulation, REE may be increased. The recommended daily caloric intake is 25 35
kcal/kg/day. Overfeeding must be avoided. In these conditions, indirect calorimetry
could be used for optimization of metabolic support. It should be noted that precise
measurement of REE by indirect calorimetry may be limited in patients receiving
RRT due to the removal of carbon dioxide by the membrane [9, 12, 13] and should be
limited to stable patients without CO
2
modifications.
Nitrogen balance has an inverse correlation with energy expenditure and is directly
associated with hospital outcome [14]. Especially for patients receiving CRRT or
using high- flux dialysates, extensive protein losses may be significant (up to 15 g of
albumin for each treatment set) [9, 11]. In this context, protein supply can move from
1.5 to 2.0 g/kg/day of protein, connected to metabolic status of patient and type of
renal replacement support. A loss of amino acids through the ultrafiltrate/dialysate
can be anticipated during CRRT and it has been estimated to be nearly 10% of overall
acid supplementation [15]. Intravenous glutamine supplementation is a part of stan-
dard care of parenteral nutrition in intensive care. During CRRT, the risk of losses
156 Kagan Singer
of glutamine is high, especially during intravenous glutamine supplementations.
Recently, recommendations of glutamine supply in critically ill patients receiving
RRT has been set to 0.5 g/kg/day (25 35 g/24 h) [16, 17].
There are several explanations for depletion of trace elements and water- soluble
vitamins in patients with AKI receiving RRT. The activity of plasma glutathione
peroxidase can be low due to a decreased synthesis in renal parenchyma, selenium
deficiency, and removal from plasma by an extracorporeal circuit. According to
Berger et al. [10], all trace elements were found in effluent fluids, but selenium had
the highest concentration. Zinc is also lost during convection or ultrafiltration, but
due to high concentrations of zinc in replacement fluid (especially in bicarbonate
solution), the total balance remains positive [9, 10]. Concentration of other trace
elements like chromium and copper are also low. Concentration of thiamine, folic
acid, and vitamin C in these patients are decreased mainly due to losses of these
micronutrients through the semipermeable membrane. Daily supplementation of
thiamine should be greater than 1.5 times the standard doses administered in par-
enteral nutrition. Vitamin C and folic acid losses can reach 100 mg/d and 600 nmol/
day, respectively, for patients receiving CRRT. Up to 150 200 mg of vitamin C is
recommended for these patients [18, 19]. On the other hand, supplementation of
fat- soluble vitamins is not recommended [9]. During continuous venovenous hemo-
filtration, glucose losses may reach up to 60 g/day. Increasing the rate of replace-
ment fluids and highest concentration of glucose can decrease glucose losses [6].
Tables 1 and 2 summarize the nutrient losses and requirements of the ICU patient
undergoing CRRT.
Extracorporeal Membrane Oxygenation
ECMO is a prolonged type of cardiopulmonary bypass and is an available technique
for short- term support of patients suffering from severe pulmonary and cardiovascu-
lar dysfunction.
Table 1. Nutrient losses during CRRT in AKI [9]
Energy Nonprotein calories 25 kcal/kg/day
2/3 of calories as glucose
1/3 of calories as lipids (11.5 g/kg/day of lipid emulsions when TPN is used)
Proteins At least 1.5 g/kg/day
Protein intake should be increased by about 0.20.3 g/kg/day to compensate for
amino acid losses during RRT
Essential and nonessential amino acids should be given when total parenteral
nutrition is used
Nutritional Imbalances during Extracorporeal Life Support 157
Patients receiving ECMO are severely ill patients. These patients are usually treated
by high doses of vasoactive agents (especially in venoarterial ECMO), need prolonged
ICU hospitalization, and receive heavy sedation and sometimes high doses steroids.
These drugs impair gastric emptying and the ability to start enteral feeding and to
reach the calorie target. Few studies have addressed nutritional support for critically
ill newborns treated by ECMO, and the same is true for adult patients, too. In one
single hospital retrospective study, Lukas et al. [20] demonstrated that most of the 48
patients receiving ECMO had inadequate nutritional support. Scott et al. [21] showed
that early enteral feeding (first 24 36 h of initiating ECMO) was well tolerated and
safe for patients treated by venovenous ECMO for severe respiratory failure. A Swiss
team [22] demonstrated that patients after cardiopulmonary bypass requiring high
doses of vasopressors tolerated enteral feeding successfully.
Accurate assessment of nutritional support may be problematic. Indirect calorim-
etry is not possible. The techniques of indirect calorimetry are based on measure-
ment of oxygen consumption (Vo
2
) and carbon dioxide production (Vco
2
), as well
as minute volume [15]. CO
2
removal across the extracorporal membrane cannot
be identified by indirect calorimetry and the level of REE during ECMO can cause
inaccuracies.
The guidelines for initiation and maintenance of nutritional support for patients
receiving ECMO are not available. The enteral route is always preferred in critical
patients, and if it can be tolerated while administrating high doses of vasopressors, it
can also be prescribed during ECMO therapy. The use of prokinetics such as meto-
clopramide and/or erythromycin is indicated, like in the general ICU population,
Table 2. Nutrient intake in AKI on RRT [9]
Amino acids Loss of up to 1020 g amino acid/day, depending on RTT modality and filter type 1015% of
infused amino acids are lost with CRRT
Glutamine Loss up to 1015% (0.56.8 g) with CVVH when supplementation level is 0.32 g/kg/day
Vitamin C Up to 600 mol/day (100 mg/day) during CVVH
Folic acid Up to 600 nmol/day during CVVH
Thiamine More than 1.5 times the daily provision of the vitamin from standard TPN solution during
CVVHD
Trace elements Selenium, chromium, copper and zinc can be loss from plasma by convection
Selenium Negative selenium balance associated with CVVH equivalent to twice the daily intake from
standard formula TPN
TPN = Total parenteral nutrition; CVVH = continuous venovenous hemofiltration; CVVHD = continuous veno-
venous hemodialysis.
158 Kagan Singer
1 Walker RJ, Sutherland WH, DeJong SA: Effect of
changing from a cellulose acetate to a polysulfone
dialysis membrane on protein oxidation and inflam-
mation markers. Clin Nephrol 2004;61:198 206.
2 Takouli L, Hadjiyannakos D, Metaxaki P, et al:
Vitamin E- coated cellulose acetate dialysis mem-
brane: long- term effect on inflammation and oxida-
tive stress. Renal Fail 2010;32:287 293.
3 Keshen TH, Miller RG, Jahoor F, et al: Stable isoto-
pic quantitation of protein metabolism and energy
expenditure in neonates on- and post- extracorporeal
life support. J Pediatr Surg 1997;32:958963.
4 Kozik DJ, Tweddell JS: Characterizing the inflam-
matory response to cardiopulmonary bypass in
children. Ann Thorac Surg 2006;81:S2347 S2354.
5 Neveu H, Kleinknecht D, Brivet F, et al: Prognostic
factors in acute renal failure due to sepsis: results of
a prospective multicentre study, the French Study
Group on Acute Renal Failure. Nephrol Dial
Transplant 1996;11:293299.
6 Metnitz PGH, Krenn CG, Steltzer H, Lang T, Ploder
J, Lenz K, Le Gall JR, Druml W: Effect of acute renal
failure requiring renal replacement therapy on out-
come in critically ill patients. Crit Care Med 2002;
30:2051 2058.
7 Wooley JA, Btaiche IF, Good KL: Metabolic and
nutritional aspects of acute renal failure in critically
ill patients requiring continuous renal replacement
therapy. Nutr Clin Pract 2005;20:176 191.
8 John S, Eckardt KU: Renal replacement strategies in
the ICU. Chest 2007;132:1379 1388.
9 Fiaccadori E, Cremaschi E, Regolisti G: Nutritional
assessment and delivery in renal replacement ther-
apy patients. Semin Dial 2011;24:169175.
10 Berger MM, Shenkin A, Revelly JP, Roberts E,
Cayeux MC, Baines M, Chiolro RL: Copper, sele-
nium, zinc, and thiamine balances during continu-
ous venovenous hemodiafiltration in critically ill
patients. Am J Clin Nutr 2004;80:410416.
11 Scurlock C, Raikhelkar J, Mechanick JI: Impact of
new technologies on metabolic care in the intensive
care unit. Curr Opin Clin Nutr Metab Care 2009;12:
196200.
12 Lev S, Cohen J, Singer P: Indirect calorimetry mea-
surements in the ventilated critically ill patient: facts
and controversies the heat is on. Crit Care Clin
2010;26:e1e9.
13 Chan LN: Nutritional support in acute renal failure.
Curr Opin Clin Nut Metab Care 2004;7:207212.
14 Scheinkestel CD, Kar L, Marshall K, Bailey M,
Davies A, Nyulasi I, Tuxen DV: Prospective ran-
domized trial to assess caloric and protein needs of
critically ill, anuric, ventilated patients requiring
continuous renal replacement therapy. Nutrition
2003;19:909916.
15 Ronco C, Ricci Z: Renal replacement therapies:
physiological review. Intensive Care Med 2008;34:
2139 2146.
16 Berg A, Norberg A, Martling CR, Garmin L,
Rooyackers O, Wernerman J: Glutamine kinetics
during intravenous glutamine supplementation in
ICU patients on continuous renal replacement ther-
apy. Intensive Care Med 2007;33:660 666.
17 Wernerman J: Clinical use of glutamine supplemen-
tation. J Nutr 2008;138:2040S 2044S.
18 Story DA, Ronco C, Bellomo R: Trace element and
vitamin concentration and losses in critically ill
patients treated with continuous venovenous hemo-
filtration. Crit Care Med 1999;27:220223.
to prefer the enteral route. If the gastric residue is larger than 500 ml and duodenal
tube is not applicable, parenteral nutrition will be prescribed. In this context, nutri-
tional support must be based on the latest evidence- based guidelines for critically ill
patients.
Conclusions
In the critically ill patient requiring extracorporeal therapy, special attention should
be given to the nutrients lost during therapy and to the inflammation induced by the
membranes. Nutritional support can replace the nutrients missing and modulate the
inflammation.
References
Nutritional Imbalances during Extracorporeal Life Support 159
19 Fortin MC, Amyot SL, Geadah D, Leblanc M: Serum
concentrations and clearances of folic acid and
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20 Lukas G, Davies AR, Hilton AK, Pellegrino VA,
Scheinkestel CD, Ridley E: Nutritional support in
adult patients receiving extracorporeal membrane
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21 Scott LK, Boudreaxus K, Thaljeh F, Grier LR,
Conrad SA: Early enteral feedings in adults receiv-
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Ilya Kagan, MD
General Intensive Care Department and Institute for Nutrition Research
Rabin Medical Center, Beilinson Hospital
IL 49100 Petah Tikva (Israel)
E- Mail ilya.kagan@gmail.com
Organ- Targeted Nutrition
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 160168
Nutrition in Pancreatitis
Stephen A. McClave
Department of Medicine, University of Louisville School of Medicine, Louisville, Ky., USA
Abstract
Severe acute pancreatitis causes an initial systemic inflammatory response syndrome (SIRS) that
drives the morbidity and mortality associated with this disease process. Failure to utilize the
gastrointestinal tract leads to loss of gut integrity and a gut- lung axis of inflammation that
generates a secondary SIRS response, further worsening patient outcome. Optimal nutrition ther-
apy involves determination of disease severity, confirming adequate volume resuscitation, achiev-
ing enteral access, and initiating feeds with an immune- modulating formula as soon as possible
after admission to the intensive care unit. Provision of early enteral nutrition is therapeutic,
changing the patients hospital course in a favorable manner.
Copyright 2013 S. Karger AG, Basel
Recommendations for nutrition therapy of the patient with severe acute pancreatitis
may be easily derived from the literature, thanks to the fact that these patients rep-
resent a well- studied homogenous patient population. While the clinical presenta-
tion varies widely, severity of the disease process can be easily measured by objective
parameters. The role of early enteral nutrition (EN) in patient management is thera-
peutic. When properly administered, EN clearly alters outcome through significant
reductions in morbidity and mortality [1].
The data supporting the value of early EN in acute pancreatitis is based on three
bodies of literature: early EN versus parenteral nutrition (PN), EN versus standard
therapy (where no specialized nutritional therapy is provided), and early versus late
EN (with the time separation at 48 h). Based on the odds ratios from two meta-
analyses of over 10 prospective randomized trials comparing EN versus PN, use of
EN reduces infection by 57%, hospital length of stay by 3.94 days, organ failure by
56%, need for surgical intervention by 63%, and mortality by 60% compared to use
of PN (p < 0.05 for all comparisons) [1, 2]. In one meta- analysis of two prospective
randomized trials, use of early EN following surgery for complications of pancreatitis
reduced mortality by 74% (p = 0.06) compared to standard therapy [1]. In the most
recent meta- analysis of 11 prospective randomized trials, EN started within 48 h
Nutrition in Pancreatitis 161
reduced organ failure by 56%, pancreatic infectious complications by 54%, and mor-
tality by 54% when compared to use of PN (p < 0.05 for all differences ) [3]. When EN
was started after 48 h, there were no significant differences in organ failure, infectious
morbidity, or mortality compared to PN [3].
Guidelines from professional medical and surgical societies around the globe are
in surprising consensus on the nutritional management of patients with severe pan-
creatitis. Due to near uniform consensus among eight society groups, over 17 rec-
ommendations were recently derived to constitute global guidelines for nutritional
therapy in pancreatitis [4]. These guidelines recommend that specialized nutritional
therapy may not be needed in mild- to- moderate disease, but with severe disease, EN
should be started early, using a small peptide medium- chain triglyceride semielemen-
tal formula, infused into the stomach or small bowel. Such therapy may be continued
in the face of complications such as ascites, pseudocysts, or necrosis, and should be
switched to PN only in the face of intolerance or insufficient delivery (failure to pro-
vide >60% goal calories after 7 days) [4].
Yet despite this strength of evidence, there is gross underutilization of this amaz-
ing therapy across the globe. Nonnutritionists tend to consider provision of EN only
if the patient is anticipated to be NPO >7 days [5]. This continued reluctance to use
EN was evident in a recent survey of practice in Australia and New Zealand which
showed that PN is still the initial mode of nutrition therapy for acute pancreatitis in
the majority of cases (58%) [6]. Gastric feeding is seldom utilized early in hospitaliza-
tion. In an international survey by the Canadian Critical Care Nutrition group, pan-
creatitis was still listed as a contraindication to EN in 8.3% of cases (Daren Heyland,
personal communication, March 2011).
Pathophysiology
Severe acute pancreatitis is a classic metabolic stress state characterized by an early
and late systemic inflammatory response syndrome (SIRS). The early SIRS response
is generated by the inflammatory process within the gland itself. The sentinel acute
pancreatitis event hypothesis suggests that while a variety of insults may trigger an
injury to the acinar cell (such as alcohol, gallstones, drugs, trauma, hypertriglyceri-
demia, etc.), a single pathophysiologic pathway evolves as the acute sentinel event [7].
The sentinel event refers not to the agent which triggers the insult, but to the viscous
cycle of inflammation which ensues. An early proinflammatory stage occurs, initi-
ated as neutrophils migrate out of the vascular space down and around the pancreatic
acinus. This may or may not be followed by a late profibrotic phase with stimulation
of stellate cells and deposition of fibrous tissue [7]. Two defects occur as a result of
injury to the acinar cell: intra- acinar activation of pancreatic enzymes (colocalization
of pancreatic zymogen with lysosomal enzymes), and inhibition of secretion (causing
the activated enzymes to be retained within the acinar cell) [7]. The sentinel event
162 McClave
leads to an elaboration of proinflammatory mediators (TNF, IL- 1, platelet activating
factor), and the recruitment and activation of inflammatory cells (such as neutrophils
and macrophages) into the gland [7]. A number of intracellular factors (calcium,
inflammatory signals, and heat shock proteins) and extracellular factors (neural and
vascular responses) influence increasing oxidative stress within the acinar cell, result-
ing in cell death either by apoptosis or necrosis [8].
A late SIRS response may be generated within days by failure to provide luminal
nutrients to the gastrointestinal (GI) tract. In the absence of luminal nutrients, quo-
rum sensing activation of virulent bacteria occurs in the GI tract [9]. There is loss of
commensal flora and adherence of the pathogenic organisms to the epithelial surface,
activating the epithelial cells to produce inflammatory cytokines. A cytokine storm
of IL- 1, TNF, and IL- 8 is released at the serosal side of the GI tract into the lymphatic
channels which pass up through the thoracic duct, the left subclavian vein, and the
pulmonary artery into the capillary bed of the lungs [9, 10]. The severity of this gut-
lung axis of inflammation is directly related to the degree of increased gut perme-
ability. Acute lung injury, acute respiratory distress syndrome, and pneumonia are the
most common complications that develop from this process [9, 10].
Provision of early EN modulates the immune responses generated in this early
and late SIRS response, resulting in attenuation of disease severity, shortening of the
disease process, heightening of antioxidant defenses, and hastening of recovery from
the disease process [1, 10].
Early Management of Acute Pancreatitis
Disease severity is determined by the presence and extent of necrosis within the gland
and by the development of multiple organ failure. Patients with severe pancreatitis may
be identified by 3 Ranson criteria, APACHE II score of 8, a CRP level of 150 mg/
dl, or Balthazar CT grade of >5 [11]. The Atlanta classification determines severe pan-
creatitis by the presence of either organ failure (shock, pulmonary insufficiency, renal
failure, or GI bleeding) or local complications (pancreatic necrosis >30%, abscess, or
pseudocysts), in the presence of unfavorable prognostic signs (3 Ranson criteria,
or APACHE II score 8) [12] (table 1). The use of antibiotics should be reserved for
overt infection. No proven beneficial effect is seen from use of nasogastric aspiration,
peritoneal lavage, surgical debridement in the absence of infection, or pharmacologic
agents such as protease inhibitor, anti- inflammatory agents, or somatostatin (to reduce
pancreatic secretion) [5]. Aggressive volume resuscitation should be undertaken and
monitored to achieve specific clinical endpoints such as a urine output of 0.5 ml/kg/h,
drop in hematocrit by >10%, central venous pressure of 8 12 mm Hg, mean arterial
pressure of 65 mm/Hg, and mean mixed venous oxygen of >65% [5] (table 1).
Enteral access may be achieved by placing a tube through the nose or mouth into
the GI tract, positioning the distal tip somewhere between the stomach and the small
Nutrition in Pancreatitis 163
bowel just below the ligament of Treitz. Gastric feeding is surprisingly well tolerated
in severe acute pancreatitis. Ease of achievement of enteral access through placement
of a nasogastric tube shortens the time to initiation of enteral feeding by a mean of
16 h (range: 12 20) [13]. In two prospective randomized trials, 5 10% of patients fed
by the gastric route experienced pain, but this incidence was no different than that of
controls fed into the jejunum [14, 15]. No change in analgesia or in the infusion rate
was required. Gastric feeding in pancreatitis is an important consideration, particu-
larly at institutions which lack the expertise of radiologists or endoscopists to achieve
deep jejunal placement (table 2).
A small peptide medium- chain triglyceride semielemental formula is most often
selected because of reduced stimulation of exocrine secretion compared to intact for-
mulas and greater absorption in a milieu of reduced pancreatic enzymes within the
lumen of the gut [16]. Patients should be monitored while on EN for two aspects of
tolerance: tolerance related to stimulation of enzyme secretion (which may be deter-
mined by the level of infusion of feeds and content of the individual formula), and
tolerance related to motility and access to the GI tract (influenced by duration of
ileus and external compression of the duodenum by an enlarged inflamed gland or
pseudocyst). While exacerbation of the SIRS response represents the most concern-
ing evidence of intolerance (which may be identified by increasing white count, fever,
worsening pain, and elevations of amylase and lipase), a simple adjustment in the
nutrition regimen such as displacing the level of infusion further down in the GI
tract or changing the content of the formula (from intact protein and long- chain fat
Table 1. Key issues in nutrition assessment
Indicators of severe disease in acute pancreatitis
Ransons criteria (3)
APACHE II score (8)
CRP >150 mg/dl
Balthazar CT grade (>5)
Atlanta classification: organ failure or local complications with unfavorable
prognostic signs (3 Ranson criteria, APACHE II score 8)
Markers of adequate resuscitation
Mean arterial pressure 65 mm Hg
Central venous oxygen saturation 70%
Mixed venous oxygen saturation 65%
Central venous pressure 812 mm Hg
Serum lactate <2 mg/dl
Base excess <5 mEq
Urine output >0.5 ml/kg/h
Decrease in hematocrit by >10%
Stable doses of pressor agents for 24 h
164 McClave
to either a small peptide medium- chain triglyceride oil semielemental formula or a
fat- free elemental formula) should promote better tolerance, and feedings can usually
be continued [16] (table 2).
Pharmaconutrition
Pharmaconutrition or immunonutrition is underutilized in severe acute pancreatitis.
While fish oil generates less inflammatory prostaglandins, leukotrienes, and throm-
boxanes than omega- 6 arachidonic acid, docosahexaenoic acid from fish oils specifi-
cally inhibits intracellular signaling, the generation of inflammatory cytokines, and
promotes a pattern of apoptosis instead of necrosis [9, 17]. Even more importantly,
fish oil decreases chemotaxis and recruitment of neutrophils into the area of the pan-
creas. Fish oil can further reduce inflammation through duodenal cholecystokinin
receptors which have a vagally mediated anti- inflammatory effect through cholinergic
pathways. Fish oil also promotes active cessation of inflammation through the genera-
tion of resolvins and protectins from eicosapentaenoic acid and docosahexaenoic acid
[9]. Fish oil can actually block the Toll- like receptor- 4 on neutrophils, macrophages,
and intestinal epithelial cells, reducing the generation of NF- kB and TNF. Fish oil
helps suppress neurogenic inflammation by altering the crosstalk between nerve end-
ings and the generation of substance P and calcitonin gene- related peptide in the area
of pancreatic necrosis. Fish oil can also help transport lipopolysaccharide endotoxin
from the gut lumen through lymphatics contained within intact chylomicrons, pro-
viding a safe means for its elimination [9].
Glutamine is particularly helpful in pancreatitis because of its ability to upreg-
ulate heat shock proteins. An increased production of heat shock proteins helps
prevent the rise in calcium within the cytoplasm of the acinar cell, prevents colo-
calization of zymogens and lysosomes, promotes apoptosis (instead of necrosis),
blocks trypsinogen activation, and reduces production of NF- kB and TNF [8, 9].
Arginine helps reset the balance with asymmetric dimethylarginine, the levels of
Table 2. Summary of principles for nutrition therapy in severe acute pancreatitis
Determine disease severity
Provide adequate analgesia
Push full volume resuscitation
Achieve early enteral access (gastric or jejunal)
Select enteral immune- modulating formula and initiate feeding
Monitor tolerance adjust content of formula or level of infusion if there is SIRS
Advance to oral diet based on clinical improvement and patient wishes
Nutrition in Pancreatitis 165
which are increased in critical illness (including pancreatitis), leading to increased
organ failure and mortality [9]. Asymmetric dimethylarginine is a vasoconstrictor
promoting reduced perfusion of tissues. Exogenous provision of arginine resets the
imbalance and helps promote vasodilation, generation of nitrous oxide, and tissue
perfusion [9].
Little progress has been made in the use of probiotics in severe acute pancreati-
tis, due to a recent unfortunate research experience. After two initial studies from
a single center showed that a combination of Lactobacillus probiotics reduced
infected necrosis and hospital length of stay as well as the SIRS response and organ
failure [18, 19], a large Dutch Propatria study utilizing higher doses of 6 probiot-
ics (Lactobacillus and bifidobacteria) fed directly into the small bowel resulted in a
higher mortality and evidence of bowel ischemia (in 6% of the patients) [20]. This
research experience was different from any other probiotic study in critical care. In
major abdominal surgery, trauma, and transplantation, use of probiotics in high-
risk patient populations has been successful in reducing infection and organ fail-
ure [21]. Fear of studying probiotics in acute pancreatitis, however, was evidenced
by a recent double- blind prospective randomized trial which was halted midway
through the study after 50 patients were entered [22]. Although CRP and immuno-
globulin levels were reduced significantly in the probiotic group, and no difference
was seen in gut permeability, hospital length of stay, or mortality between groups,
the study was stopped prematurely simply because of the experience in the Dutch
Propatria study [22].
Use of Parenteral Nutrition
Use of PN has a clear role in the management of patients with severe acute pancrea-
titis where EN is not feasible or is insufficient to meet goals after some designated
period of time. Early experience from a study by Sax et al. [23] showed that PN pro-
vided in the first 24 h following admission worsened outcome compared to standard
therapy. In a subsequent study from China, PN provided after 3 or 4 days showed
improved outcome with less infection, reduced organ failure, and shorter length of
stay compared to standard therapy [24]. The decision to initiate PN should be based
on the status of EN feeding (being considered when EN provides less than 60% of goal
calories), and timing with respect to days following admission to the intensive care
unit (initiation considered after 4 or 5 days). The optimal timing of initiation of PN
and the point at which EN is considered to be insufficient has not been determined at
this time. Disease severity and patient nutritional status (prior weight loss or weight
below 90% ideal body weight) are clearly factors in the decision to initiate PN. Once
PN is initiated, a mix- fuel regimen including lipids should be utilized, moderate con-
trol of glucose should be employed, and triglyceride levels should be monitored and
kept below 400 mg/dl.
166 McClave
Advancement to Oral Diet
Surprisingly, few recommendations exist to tell the clinician when to advance to oral
diet. Approximately 20% of patients will flare in response to advancement to oral
diet, a group that is difficult to predict from the rest [25]. Surprisingly, advancement
does not require clear liquids first, as a soft diet or low- fat solid diet may be tolerated
as well or better. In one randomized trial, advancement to a soft diet reduced hos-
pital length of stay compared to advancement first to clear liquids [26]. While some
recommendations have been published suggesting that absence of pain and normal-
ization of amylase are required prior to advancing to oral diet, in a randomized fash-
ion one study showed that a patients wishes were a better indicator of successful
advancement [27]. In fact, using the patients wishes as an indication to advance the
diet succeeded in reducing hospital length of stay compared to more rigid clinical
guidelines [27].
Future Considerations
How to optimally manage the nutrition therapy of patients with mild- to- moderate
acute pancreatitis is not clear. Over the past decade, eight international societies have
stated that for patients with mild- to- moderate pancreatitis, no specialized nutri-
tion therapy (EN or PN) is indicated [4]. The ability of clinicians to differentiate
severe pancreatitis from mild- to- moderate disease, however, is poor. The sensitiv-
ity of clinical assessment to identify the patient with severe pancreatitis on admis-
sion has been shown to be 34 44%, rising only to 50 66% after 72 h [28]. Objective
scores by APACHE II or Ranson criteria achieve only a 75% sensitivity after 48 72 h
[28]. Thus, some patients presumed to have mild- to- moderate disease on admission
may in fact turn out to have severe disease. It is possible that patients with mild-
to- moderate pancreatitis might actually benefit from early nutrition therapy and
maintenance of gut integrity. In the Enhanced Recovery after Surgery (ERAS) pro-
gram in Europe, patients undergoing colonic resection (which would be expected to
generate only mild- to- moderate surgical stress) have been shown to have surprising
improvement in outcomes by aggressive nutritional management [29]. Such innova-
tive aggressive nutrition strategies applied to patients with mild- to- moderate pan-
creatitis might conceivably reduce hospital length of stay and promote faster return
to baseline function.
Greater use of pharmaconutrition should be explored in the future. Strategies to
stimulate the bodys own endogenous system for antioxidant defense, the antioxidant
response elements, have been shown in the past to be activated to specific nutrients
(such as sulforaphane in broccoli, resveratrol in blueberries, and polyphenols in cau-
liflower) [9]. Targeting the transcription factors involved in antioxidant response ele-
ments would help encode antioxidant proteins such as glutathione transferase and
Nutrition in Pancreatitis 167
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7 Schneider A, Whitcomb DC: Hereditary pancreati-
tis: a model for inflammatory diseases of the pan-
creas. Best Pract Res Clin Gastroenterol 2002;16:
347 363.
8 Pandol SJ, Saluja AK, Imrie CW, Banks PA: Acute
pancreatitis: bench to the bedside. Gastroenterology
2007;132:1127 1151.
9 McClave SA: Drivers of oxidative stress in acute
pancreatitis: the role of nutrition therapy. ASPEN
Presidential Address. JPEN J Parenter Enteral Nutr
2012;36:24 35.
10 Jabbar A, Chang WK, Dryden GW, McClave SA:
Gut immunology and the differential response to
feeding and starvation. Nutr Clin Pract 2003;18:
461 482.
11 Wilson C, Heads A, Shenkin A, Imrie CW:
C- reactive protein, antiproteases and complement
factors as objective markers of severity in acute pan-
creatitis. Br J Surg 1989;76:177 181.
12 Bradley EL III: A clinically based classification sys-
tem for acute pancreatitis. Summary of the
International Symposium on Acute Pancreatitis,
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13 Marik PE, Zaloga GP: Gastric versus post- pyloric
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bolster the bodys own antioxidant defense system [9]. A similar effect might be
achieved by a different mechanism through the alteration of epigenetics by dietary
factors which influence methylation and histone transferases [9]. Providing zinc or
copper to stimulate histone transferase might conceivably activate genes responsible
for encoding the same enzyme glutathione transferase. Providing folate, betaine, or
vitamin B
12
as methyl donors might reduce oxidative stress by turning off (through
methylation) TNF- promoter genes [9].
Earlier more aggressive strategies could be adapted to enhance nutrition therapy
at the onset of the disease, accomplished by providing enteral glutamine during the
resuscitation phase in the emergency room soon after admission for severe acute pan-
creatitis. Such practice in trauma patients has been shown to maintain gut integrity,
stimulate contractility, and improve tolerance once enteral formula is provided on
subsequent days [30]. Establishing enteral access via a simple nasogastric tube in the
emergency room would facilitate advancement from the enteral glutamine to formula
once adequate resuscitation has been documented. And finally, clearer guidelines
are needed in the future to know exactly when supplemental PN should be provided
when EN is insufficient.
References
168 McClave
14 Eatock FC, Chong P, Menezes N, Murray L, McKay
CJ, Carter CR, et al: A randomized study of early
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432 439.
15 Kumar A, Singh N, Prakash S, et al: Early enteral
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21 McClave SA, Martindale RG, Vanek VW, McCarthy
M, Roberts P, Taylor B, Ochoa JB, Napolitano L,
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24 Xian- li H, Qing- jiu M, Jian- guo L, Yan- kui C, Xi- lin
D: Effect of total parenteral nutrition (TPN) with
and without glutamine dipeptide supplementation
on outcome on severe acute pancreatitis (SAP). Clin
Nutr Suppl 2004;1:43 47.
25 Lvy P, Heresbach D, Pariente EA, Boruchowicz A,
Delcenserie R, Millat B, et al: Frequency and risk
factors of recurrent pain during refeeding in patients
with acute pancreatitis: a multivariate multicentre
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Mahukar S, Reddy DN: Clinical trial: oral feeding
with a soft diet compared with clear liquid diet as
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Pharmacol Ther 2008;28:777 781.
27 Teich N, Aghdassi A, Fischer J, Walz B, Caca K,
Wallochny T, et al: Optimal timing of oral refeed ing
in mild acute pancreatitis: results of an open
randomized multicenter trial. Pancreas 2010;39:
1088 1092.
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come in acute pancreatitis: a comparative study of
APACHE II, clinical assessment and multiple factor
scoring systems. Br J Surg 1990;77:1260 1264.
29 Lassen K, Soop M, Nygren J, Cox PB, et al:
Consensus review of optimal perioperative care in
colorectal surgery: enhanced recovery after surgery
(ERAS) recommendations. Arch Surg 2009;144:
961 969.
30 McQuiggan M, Kozar R, Sailors RM, Ahn C,
McKinley B, Moore F: Enteral glutamine during
active shock resuscitation is safe and enhances tol-
erance of enteral feeding. JPEN J Parenter Enteral
Nutr 2008;32:28 35.
Stephen A. McClave, MD, Professor of Medicine
Division of Gastroenterology, Hepatology and Nutrition
University of Louisville School of Medicine
Louisville, KY 40202 (USA)
Tel. +1 502 852 7963, E- Mail Stephen.McClave@louisville.edu
Organ- Targeted Nutrition
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 169178
Which Nutritional Regimen for the Comorbid
Complex Intensive Care Unit Patient?
Pierre Singer
a
Hadas Weinberger
b
Boaz Tadmor
a
a
Rabin Medical Center, Beilinson Hospital, Petah Tikva, and
b
Holon Institute of Technology, Holon, Israel
Abstract
Intensive care patient nutritional therapy has been standardized by guidelines for decades. However,
the same nutritional regimen to such a heterogeneous population seems a difficult task. These
patients have various genotypes, numerous comorbidities, different severities and lengths of acute
illness, and multiple interventions. Therefore, a new way of approaching the complexity of these
patients is required, progressing from the whole body to compartments, organs, pericellular space,
and cellular metabolism. We propose to untangle the complexity of intensive care unit patients by
analyzing the complexity and deciding on the appropriate measures. These activities should aim
towards personalized identification and prediction of adequate recovery measures, considering the
generalization of guidelines based on the accumulated experience. Defining the specific nutrition
supplement to affect various body niches could produce a significant contribution to the monitor-
ing of nutritional complications, better understanding of the published nutritional interventions,
and wise use of the nutritional tool in the complex patient.
Copyright 2013 S. Karger AG, Basel
Comorbidities have become very frequent in the intensive care setting, associating
chronic diseases such as diabetes mellitus type 2, cardiomyopathy, chronic renal fail-
ure, and obesity to cured cancer, as well as new acute illness such as sepsis second-
ary to community- acquired pneumonia requiring mechanical ventilation. In a recent
Danish study [1], preadmission morbidity level was present in 51.5% (low), 34.1%
(moderate), and 14.4% (high) of intensive care unit (ICU) patients, increasing the
mortality in the high- morbidity level by 5.1% during the second and third year of
follow- up of more than 28,000 patients. While the metabolic and nutritional con-
dition patients may change as they transition through acute illness, persistent acute
critically illness, chronic critically illness, and hopefully recovery as described by
Schulman and Mechanick in another chapter of this book [pp. 6981], the question of
adequate nutritional support in such complex patients has not been solved in the lit-
erature. We propose a decision- making approach mixing the condition of the patient,
170 Singer Weinberger Tadmor
his priorities, and the severity of organ failures, as well as his progression to the dis-
ease, to solve this emerging problem. Comorbidity has been defined by the Charlson
comorbidity index, which has a good predictive value in the ICU, as well as in general
wards [2, 3]. The aim of this chapter is to describe the most frequent comorbid con-
ditions and their nutritional implications and to try to give a frame to the decision-
making process of the complex ICU patient.
Comorbidities
Age and Longevity
Acute disease, bed rest, or inactivity associated with hospitalization threaten the
muscle tissue and functional activity. In the absence of nutritional therapy, lean body
mass loss is inevitable in these conditions and is increased in the elderly. Kortebein
et al. [4] observed a loss of 0.95 kg of lean leg mass following 10 days of bed rest in
older adults. General agreement exists that increasing daily protein intake beyond
0.8 g/kg/day may enhance muscle protein anabolism, providing a means of reduc-
ing the progressive loss of muscle mass with age [5, 6]. A new concept, frailty in the
critically ill [7], has been developed recently and is defined as a multidimensional
syndrome characterized by the loss of physical and cognitive reserve, predisposing to
the accumulation of deficits and increased vulnerability to adverse events. Frailty is
of course correlated with age, but is added to other burdens of comorbid diseases and
disabilities. The patient is unable to move and loses strength and endurance together
with his nutritional reserve. The prevalence of frailty in the ICU is not yet known, but
seems to be quite frequent. Individualized nutritional, physical, psychological, and
social interventions may be the basis for efficient therapy. Following this concept, a
PIRO (predisposition, injury, response and organ dysfunction) score was developed
[8]. The comorbidity includes chronic obstructive lung disease and immunosuppres-
sion, as well as age >70 years. In PIRO scores obtained from 529 patients, 49% had a
comorbidity and 31% were older than 70 years.
Guadagni and Biolo [9] described that in inactivity and diseases associated with
systemic inflammation, dietary proteins are not able to reach protein anabolism,
whereas physical exercise ameliorates the efficiency in using these dietary proteins.
While 1.2 g/kg/day is recommended for inactive healthy individuals, 1.5 g/kg/day is
recommended in patients with severe systemic inflammation, like in critical illness,
to decrease whole body protein wasting.
Obesity or Severe Malnutrition
Overweight, obesity, and severe morbid obesity as well as insulin resistance have
become an integral part of our horizon in the ICU. BMI has a U- shaped associa-
tion with mortality, the lowest mortality being in overweight and obese patients [10].
However, lean body mass may vary considerably. Elderly sarcopenic obese patients
Nutritional Regimens for Comorbid Complex ICU Patients 171
may hide the real decrease in lean body mass they experience. In acute disease like
acute myocardial infarction and acute heart failure, the prognosis is better despite the
fact that obesity is a risk factor in ischemic heart disease. This example illustrates the
complexity of comorbidity: obesity is a risk factor increasing length of stay, length of
ventilation, infections, and pressure sores in the ICU, but could improve outcome in
specific diseases. Weight is usually wrong in obese patients. Estimation causes even
more mistakes. Therefore, use of predictive equations may be inaccurate. Multiple
studies demonstrate an unacceptable variability between resting energy expenditure
measured by indirect calorimetry and predictive equations [11]. Therefore, when
possible, indirect calorimetry should be performed (table 1). Recommendations for
nutritional support have been proposed by the ASPEN guidelines [12], but only a
few prospective randomized studies are available. Following the studies by Dickerson
et al. [13], a hypocaloric hyperprotein diet has been proposed to improve morbidity
(length of ventilation and length of stay, as well as insulin requirements). No improve-
ment in mortality was observed.
In a population of 796 surgical ICU patients [14] older than 60 years and having
normal weight or underweight, the overall mortality was higher in the undernour-
ished patients (16.1 vs. 10.5%) despite a similar APACHE III score and a simi-
lar length of stay score (6.7 vs. 5.8 days). These results are similar to those from
Table 1. Nutritional complications and recommendations related to comorbidities
Nutritional
complications
Proposed intervention
calories protein specific nutrients
Obesity insulin resistance IC
1114 kcal/kg ABW
2225 kcal/kg IBW
2.02.5 g/kg high fiber,
low carbohydrate load
Elderly sarcopenia IC
2025 kcal/kg IBW
high doses,
leucine
Renal
failure
protein loss IC 1.2 g/kg/day EAA
Cancer cachexia IC fish oil, HMB,
arginine, glutamine
Sepsis protein energy
malnutrition
IC
2530 kcal/kg/day
1.5 g/kg/day fish oil?
BMI <16 severe malnutrition IC start with
10 kcal/kg/day
refeeding
HMB = Hydroxymethyl butyrate; IC = indirect calorimetry; IBW = ideal body weight; ABW = actual
body weight.
172 Singer Weinberger Tadmor
Alberda et al. [15] showing an increase in mortality in underweight or very obese
patients. However, the weight evaluation is not easy in the ICU. A decrease in lean
body mass and an increase in extracellular water increase the difficulties in evalu-
ating this actual weight. Alternatives use ideal weight based on height, or more
sophisticated tools such as DEXA or ultrasound to evaluate muscle and fat mass
[16].
Cancer and Immune Suppression
Again, predictive equations make poor evaluation when compared to measured rest-
ing energy expenditure using indirect calorimetry [17]. Fifteen percent are overfed
and 15% are underfed if the predictive equations are used. In 1,410 subjects undergo-
ing major abdominal surgery for gastrointestinal cancer and receiving various types
of nutritional support, Bozzetti et al. [18] found that the factors related to compli-
cations at multivariate analysis were pancreatic surgery, age, weight loss (p < 0.02),
low serum albumin, and nutritional support (p < 0.001). Immune- enhanced enteral
nutrition significantly reduced postoperative morbidity.
Patients suffering from head, neck, and esophageal cancers are malnourished and
it has been proven that percutaneous gastrostomy is efficient to supply the protein-
energy requirements and decrease the complication rate [19]. Among gynecologic
cancer patients, the prevalence of malnutrition is about 20% at the time of diagnosis
and it has been suggested that 20% of these patients die from the effects of malnutri-
tion rather than from the malignancy itself [20]. The benefits of nutritional support
are discussed in this condition.
In the ICU, patients who die from sepsis suffer from immunosuppression con-
firmed by biochemical, flow cytometry, and immunohistochemical findings.
Extensive depletion of splenic CD4, CD8, and HLA- DR cells, as well as depletion
of expression of ligands for inhibitory receptors on lung epithelial cells, have been
observed [21].
Organ Failures
Taken separately, the ASPEN/SCCM [22] or the ESPEN guidelines [23, 24] regard-
ing organ failure are possible to follow (table 1): patients with hemodialysis or con-
tinuous renal replacement therapy should receive 2.0 2.5 g/kg/day of protein and
should not be restricted in protein. Patients with chronic liver failure should not
be restricted with protein, and only those refractory to standard therapy should
receive branched- chain amino acids. Patients suffering from acute lung injury or
acute respiratory distress syndrome should receive an enteral diet enriched in n- 3
fatty acids and - linoleic acid. However, nobody has studied the post- liver trans-
plant patient suffering from malnutrition, acute renal failure, and acute respiratory
failure after massive transfusion, for example. Therefore, a new approach that is
more personalized and based more on a genotype approach should be proposed
(fig. 1).
Nutritional Regimens for Comorbid Complex ICU Patients 173
How to Deal with the Complexity?
The question of adequate nutrition support for the complex patient has two dimen-
sions: on the one hand are morbidities and associated nutrition support, while on the
other hand there is the metabolic and nutritional condition of the patient as well as
the actions to be advised and monitored in this context.
Currently, the management of nutrition for the comorbid patient, much like
the management of complex patients, lacks personalized support of both adequate
decision- support systems and medical technologies [25]. An attempt towards a meth-
odological approach supporting the personalized monitoring of comorbid conditions
and their nutritional implications should consider the bidimensional view of the situ-
ation at hand: the complex patient and nutritional guidelines.
The Complex Patient
Previous research described the four facets by which the complex- patient can be iden-
tified [26]. The first is multimorbidity, summoning interward and interprofessional
intervention. This means the identification of morbidities and the analysis of associ-
ated risks. In the context of the discussion here, this means the analysis of patient
data for the identification of the metabolic and nutritional condition of the patient.
Second is what is often found to be a lack of corresponding evidence- based medicine,
shortage or inadequate coverage of the electronic patient record, and the scarcity of
information or organizational clinical guidelines. This shortage might threaten recov-
ery. Third, is the summoning together of experts in the medical community together
with those of affiliated experts groups for the balanced consideration of treatment
opportunities and threats. In the context of this chapter, this could mean the inclu-
sion of a nutrition expert man or machine. Fourth, we reference the physician as
the case manager who assumes the leader role in view of the comorbid condition
of the complex patient. This requires professional competency for the negotiation of
Morbidities
Cancer
t%JBHOPTJT
t4VSHFSZ
t3BEJPUIFSBQZ
t$IFNPUIFSBQZ
3FOBMGBJMVSF
-JWFSGVODUJPOEJTUVSCBODFT
3FTQJSBUPSZEJTFBTFT
&MEFSMZ
t4BSDPQFOJB
t.BMOVUSJUJPO
OCFTJUZ
t.FUBCPMJDTZOESPNF
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Fig. 1. Comorbidities.
174 Singer Weinberger Tadmor
the multicriteria decision- making situation. Ambiguity, amongst other decision ele-
ments, might consequently provoke discrepancy between a physicians skills, attitude,
and values, and between patient safety and the quality of care.
Towards a Model for Untangling Complexity
There could be several ways to support decision- making for balancing patient nutri-
tional condition, borrowing on domains other than the medical domain. An example
is designing a triangular model of an ontology- based business process [27, 28], illus-
trated using notions previously discussed in this chapter. Following the physicians
perspective, the goal set for this ontology is supporting decision- making for balanc-
ing patient nutritional condition.
There are three upper- level classes in this ontology (fig. 2): resources, which rep-
resent proposed interventions and predictive equations or indirect calorimetry; tasks,
which represent the monitoring of nutrition complications and morbidities; and agents,
which represent metabolic and nutritional conditions of the patient and risks (fig. 1).
Currently, only upper- level classes (concepts) and subclasses of this ontology have been
introduced. Example extension options for this representation, such as using attributes
(i.e. qualities) and behavior, as well as relationships, are illustrated as well.
Proposed intervention
tEnergy
t1SPUFJO
t4QFDJDOVUSJFOU
t.JDSPOVUSJFOU
1SFEJDUJWF
FRVBUJPOTPSJOEJSFDU
DBMPSJNFUSZ
3FTPVSDFT
.FUBCPMJDBOE
OVUSJUJPOBMDPOEJUJPO
PGUIFQBUJFOU
t"DVUFJMMOFTT
t1FSTJTUFOUBDVUF
DSJUJDBMMZJMMOFTT
t$ISPOJDDSJUJDBMMZ
JMMOFTT
t3FDPWFSZ
Risks
t0SHBOGBJMVSF
t*NNVOFTVQQSFTTJPO
t4FWFSFNBMOVUSJUJPO
Agents
.POJUPSJOHOVUSJUJPO
DPNQMJDBUJPOT
t1FSTPOBMJ[FE
FWBMVBUJPO
.PSCJEJUJFT
t$ISPOJDEJTFBTFT
t$BODFS
t&MEFSMZ
t0CFTJUZ
t4FQTJT
5BTLT
Fig. 2. Ontology of comorbidity conditions and nutritional implications.
Nutritional Regimens for Comorbid Complex ICU Patients 175
Resources
There are two upper- level classes modeled as resources. These are (1) proposed inter-
ventions, and (2) predictive equations or indirect calorimetry. Proposed interventions
describe the specific intervention type, such as energy, protein- specific nutrients, and
micronutrients. Energy is both a part of this group and the vehicle used to create the
latter ones. Predictive equations are used for the monitoring of useful interventions.
Agents
There are two upper- level classes modeled as agents. These are metabolic and nutri-
tional conditions of the patient, and risks consisting of organ failure, immune sup-
pression, and severe malnutrition. Risk factors, much like any other concept, should
also be considered in context. For instance, obesity (as previously described in this
chapter) can be considered as a risk factor, yet might also support recovery.
An example role (i.e. behavior) in this context is the instructing nutrition path, i.e.
the monitoring of nutrition complications represented under tasks.
Task
There are two upper- level classes describing monitoring nutrition complications and
morbidities, such as chronic diseases, cancer, elderly, obesity, and sepsis. Monitoring
nutrition complication is focused on a personalized and adapted evaluation in view
of the morbidities characteristic of the individual patient. Morbidities trigger specific
human body behavior, while calling upon physicians action towards recovery.
An example modeling dilemma can be seen with obesity. While notions such as
overweight, severe morbid obesity, and insulin resistance could be represented as
subclasses, they could also be represented as either attributes or behavior. This is to be
resolved subject to the practitioners evaluation.
Monitoring Nutrition Complications at the Intensive Care Unit
The task perspective of the ontology formerly discussed represents the monitoring of
nutritional complications based on personalized evaluation and prediction rules.
Physicians at the ICU are requested to understand and react accurately in real
time to the hyperacute phase of comorbidities, as exemplified in the complex
patient case. However, although this is meant to affect patient safety and the qual-
ity of care, not all the dimensions of the perceived action are supported by medical
technology.
This section is dedicated to the discussion of the processes constituting the dynamic
dimension of the suggested ontology, excluding prediction rules. A framework is sug-
gested, designed to maintain personalized nutrition support. This is to be considered
in the context of the bidimensional view of the five- niche lattice of the human body
and the associated monitoring and evaluation processes (table 2).
176 Singer Weinberger Tadmor
From Hyperacute Changes to Hyperacute Reaction
There are several critical molecular deviations that can be considered as facilitators of
metabolic pathways. These are represented as the five- niche of the human body and
associated monitoring and evaluation processes. The latter should be adjusted to the for-
mer by evaluation parameters (table 2). Consequently, the adapted management of this
process constitutes the backbone of comorbidity nutrition complication adaptation.
Personalized Nutritional Support Process
Comorbidities are common final pathways for diverse molecular, metabolic, and phys-
iologic modifications, and are recognized at different body niches. Understanding the
complexity of the equilibrium or disequilibrium of this multifaceted phenomenon
could shed light on a spectrum of questions, hindering the amelioration of patient
outcome recognized by lowered mortality and morbidity. Two possible contributing
interventions might be seen with yet another approach at clinical staging and evalua-
tion suggested here based on molecular- metabolic- physiologic parameters.
Guidelines could be advised to support the iterative procession of understanding and
on- time reaction. The suggested activities described here illustrate an example approach
to monitoring and evaluation processes as presented in table 2. These activities are:
1 Defning patient medical and nutritional status according to metabolic and
physiologic criteria
2 Understanding the generic, current, relevant trends in patient metabolic and
physiologic pathways
3 Identifcation of personalized best practices towards patient reaction and drug
utilization with relation to micro- and macronutrients support
4 Defne the best available ways to follow and predict the outcome of the external
involvement and support
5 Searching for real, rather than surrogate markers to underline needed changes
6 Evaluate the complex adaptive systems of the above in the earliest and most
accurate fashion.
The first two activities are complementary, with the analysis of current status on
the one hand, and the search for appropriate measures on the other. The third and
Table 2. Adaptation of comorbidity nutrition interrelations
Monitoring perspective Physiologic
evaluation
Metabolic
evaluation
Pathologic
imaging
Molecular
evaluation imaging
Cellular
Pericellular space
Compartment
Organ layer
Entire human body
Nutritional Regimens for Comorbid Complex ICU Patients 177
1 Christiansen CF, Christensen S, Johansen MB,
Larsen KM, Tonnesen E, Sorensen HT: The impact
of pre- admission morbidity level on 3- year mortal-
ity after intensive care: a Danish cohort study. Acta
Aneasthesiol Scand 2011;55:962 970.
2 Poses RM, McClish DK, Smith WR, Bekes C, Scott
WE: Prediction of survival of critically ill patients
by admission comorbidity. J Clin Epidemiol 1998;
49:743 747.
3 Christensen S, Johansen MB, Christensen CF,
Lemshow S: Comparison of Charlson comorbidity
index with SAPS and APACHE scores for predic-
tion of mortality following intensive care. Clin
Epidemiology 2011;3:203 211.
4 Kortebein P, Ferrando A, Lombeida J, et al: Effect of
10 days of bed rest on skeletal muscle in healthy
older adults. JAMA 2007;297:1772 1774.
fourth activities aim at personalized identification and prediction of adequate recov-
ery measures. The latter two activities, again, aim at the generic level of handling
complex patient situations, i.e. considering the generalization of guidelines based on
the accumulated experience.
Conclusions: The Gaps and the Challenges
Challenges still lie ahead in understanding and advising medical technology for the
monitoring and evaluation of the five niches of the human body for constant changes
(predictable and unpredictable). Consequently, adequate evaluation technologies
should be advised and parameters defined. Furthermore, the relationships between
nutritional complications and each body layer should be considered.
As evident in table 2, not all levels of inquiry are supported by medical technol-
ogy. This gap calls for further research on issues such as the evaluation of cellular and
microlevel physiologic and metabolic evaluation. ICU physicians, however, could be
educated to recognize these inquiry pathways in order for them to maintain personal-
ized nutritional support, i.e. identify, define, and resolve comorbidity situations and
corresponding nutrition complications.
A personalized approach entails the simultaneous definition of different critical
parameters at different scales and levels, acknowledging perceived modifications for each
niche of the human body (e.g. cellular) in accordance with the corresponding monitor-
ing activities (i.e. physiological, metabolic, pathological, and molecular perspectives).
A matrix should be advised to suggest the relationships (e.g. priorities and prediction
rules) between resources, agents, and tasks in the suggested ontology. These relation-
ships should define such aspects as hierarchy between events and tasks. Defining the
specific nutrition supplement to affect various body niches could result in a significant
contribution to the monitoring of nutritional complications, consequently paving the
way towards an innovative nutrition support paradigm. Untangling complexity entails
not only the identification and the understanding of proposed interventions, but also
the holistic ontological perception of the human body and monitoring process.
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Pierre Singer, MD
Critical Care Medicine, Institute for Nutrition Research
Rabin Medical Center, Beilison Hospital
IL 49100 Petah Tikva (Israel)
Tel. +972 3 9376521, E-Mail psinger@clalit.org.il
Organ- Targeted Nutrition
Singer P (ed): Nutrition in Intensive Care Medicine: Beyond Physiology.
World Rev Nutr Diet. Basel, Karger, 2013, vol 105, pp 179189
Nutrition Support for Wound Healing in
the Intensive Care Unit Patient
Miriam Theilla
Intensive Care Unit, Rabin Medical Center, Petah Tikva, Israel
Abstract
The integumentary system is not considered immediately vital to the survival of the acutely and
critically ill patient. The skin, however, is a vibrant organ that functions as a physical and immuno-
logical barrier between the external world and the sterile underlying tissues. Preclinical and observa-
tional studies depict the deleterious effect of insufficient energy, protein, and micronutrients on
wound healing and on pressure ulcer (PU) burden, and demonstrate that serious PUs raise patients
daily energy expenditure. In addition, several randomized controlled trials (RCTs) have assessed the
impact of a nutritional intervention on the incidence and healing of PUs. RCTs have been heteroge-
neous vis- - vis patient population and healthcare setting, methodological quality, type (e.g. single
vs. multiple nutrients) and duration of nutritional support, method of PU assessment, etc. Most stud-
ies evaluate oral supplementation in hospitalized patients and institutionalized elderly. The paucity
of RCTs focusing on intensive care unit (ICU) nutrition in the support of wound healing and the pre-
vention of pathologic healing precludes formulation of evidence- based guidelines for clinicians.
Nevertheless, supplying ICU patients with at- least the required quantities of calories, protein and
micronutrients (in accordance with ICU nutrition guidelines) can be endorsed with sufficient cer-
tainty, in order to prevent and treat PUs. Initial evidence suggests that immunonutrition that includes
long- chain omega- 3 fatty acids may prove to be cost- effective in preventing PUs in high- risk patients,
and in treating existent ulcers. Copyright 2013 S. Karger AG, Basel
Wound Healing and Pressure Ulcers in the Intensive Care Unit
Wound healing is the complex multistage process by which tissue continuity, integ-
rity, and function are restored following injury or infection. This physiologic repair
response requires a dynamic temporal and spatial interplay of several cell types,
including local parenchymal and mesenchymal cells as well as resident and recruited
hematopoietic cells. The process comprises a regulated series of events, commencing
with an initial inflammatory response to injury. Most texts describe three distinct, yet
partially overlapping (in time) phases of wound healing. Inconsistency exists regard-
ing the designation of the two postinflammatory phases, which have been referred to
180 Theilla
as the tissue formation and tissue remodeling phases [1], proliferation and remodel-
ing phases [2], etc. For simplicity, the postinflammatory phases of wound healing are
referred to in this text as a single reparative- anabolic phase.
In general, the healing of wounds involving the skin, bones, viscera, etc., follows a
similar sequence of events. The ability to heal wounds emerges in utero, at which time
injured fetal tissues can be accurately regenerated. In contrast, the repair response in
human adults typically results in the formation of some fibrotic scar tissue, i.e. con-
nective tissue that replaces the original, functional tissue. Although healing by fibrosis
maintains tissue continuity, in excess it hampers function of the organ. Nonhealing
wounds lie at the other extreme of the pathologic healing spectrum [2].
The healing of several types of wounds is of relevance to clinical nutrition in vari-
ous intensive care unit (ICU) settings. Severe trauma typically incurs musculocu-
taneous and visceral injury. Burns degrade the cutaneous barrier with the external
environment and may reach deeper tissues; extensive burns are also inductive of
catabolism and inflammation. Surgical and mixed ICUs handle patients experienc-
ing or at risk of wound dehiscence and anastomosis leak, both of which are forms
of failure to heal. Nonhealing enterocutaneous fistulas often arise in patients with
underlying malnutrition, and fistulas negatively influence both nutritional require-
ments and delivery. In addition, many ICU patients suffer chronic comorbidities
which predispose to nonhealing cutaneous wounds (e.g. foot ulceration in diabetes
mellitus) [3]. Nutritional management of surgical patients, of patients with burns,
trauma, and enterocutaneous fistulas has been reviewed elsewhere (e.g. see the vari-
ous sections of the ESPEN Guidelines on Enteral and Parenteral Nutrition). Patients
with a critical illness are also at excess risk of presenting with and/or developing pres-
sure ulcers (PUs) [4], which is the focus of this chapter.
A PU, occasionally referred to as a decubitus ulcer or the colloquial term - bed sore,
is defined as an area of localized damage to the skin and underlying tissue caused by
pressure, shear, friction, or a combination of these [4]. Skin and soft- tissue breakdown
generally results from prolonged compression between a bony prominence and an
external surface. Indeed, reduced mobility is a leading risk factor for PU. Moisture, such
as that resulting from urinary/fecal incontinence, exacerbates skin breakdown in the
presence of the aforementioned mechanical factors. Other risk factors include chronic
diseases, sensory impairment, compromised skin perfusion . . . and malnutrition! [4].
There are several methods of grading PU severity. In order to standardize diagnosis,
research and management the EPUAP and NPUAP [European and National (North
American) Pressure Ulcer Advisory Panels] endorse a four- level category- staging sys-
tem of increasing severity [5]. Intact skin with nonblanchable redness of a localized
area, usually over a bony prominence, is designated as a category- stage I (also referred
to as grade I) PU, whereas category- stage IV indicates full thickness tissue loss with
exposed bone, tendon, or muscle. Another grading system, the Pressure Ulcer Scale for
Healing (PUSH) tool was developed by the NPUAP as a quick, reliable tool to monitor
the change in PU status over time. The PUSH tool is a useful clinical aid to monitor the
Nutrition Support for Wound Healing 181
three critical parameters that are the most indicative of PU healing length width,
exudate amount, and type of tissue (from closed to necrotic tissue) [6].
The incidence and prevalence of PUs in the ICU and other healthcare settings vary
considerably between studies. For instance, prevalence rates of PUs are reported to be
14 42% [7 9]. Variability of rates notwithstanding, PUs are more common in adult
ICUs than in other hospital departments [10], a consequence of converging risk fac-
tors in the acute critically ill patient (fig. 1).
Nutrients and Wound Healing
In an otherwise healthy mammal, the successful healing of a serious wound requires
an adequate and continuous supply of energy- providing macronutrients, protei-
nogenic amino acids, and essential micronutrients, particularly zinc, vitamin C,
Underlying critical
illness, underlying
chronic illnesses
Negative ICU
and long-term
outcomes
E
n
e
rg
y,
p
ro
te
in
, a
n
d
m
icro
n
u
trie
n
t
re
q
u
ire
m
e
n
ts
E
n
e
rg
y,
p
ro
te
in
, a
n
d
m
icro
n
u
trie
n
t
su
p
p
ly
F Incidence, f healing
of PUs
Immobility, incontinence,
f skin perfusion,
oxygenation
F PU burden
?
Fig. 1. Interrelationship between critical illness, PUs, and nutritional requirements. The incidence
and prevalence of PUs is higher in the ICU that in most other hospital departments. Many patients
present with PUs upon admission. Furthermore, acute critical illness per se predisposes to PUs and
often compromises dermal perfusion and blood oxygenation, increasing the skins susceptibility to
the mechanical factors responsible for PU. In addition, the typical ICU patient suffers from reduced
mobility, and often from incontinence, which contribute to the breakdown of skin and underlying
tissues. Acute critical illness is usually associated with increased requirements for energy, protein,
and micronutrients, relative to supply. The healing of significant PUs is itself energy- , protein- , and
micronutrient- demanding, and is negatively influenced by an insufficient supply. Accumulation of
nutrient/energy debt is associated with negative ICU outcomes, and ICU patients with PUs also
experience unfavorable outcomes. These complex interrelationships underscore the importance of
nutritional support in the ICU patient, plausibly attenuating thereby the development of PUs and
enhancing the healing of existing ones. Bold, large arrows indicate causal association; , denote
increases and decreases, respectively.
182 Theilla
and vitamin A. Conceptually, the contribution of energy and nutrients to the heal-
ing process is readily appreciated when considering that both the inflammatory and
reparative- anabolic stages of wound healing entail considerable cell division, syn-
thesis of structural proteins and enzymes, performance of other ATP- requiring pro-
cesses, and as essential cofactors for enzymes that are upregulated during wound
healing; hence, the increased demand for energy and nutrients that builds cells and
tissues. This is evident from studies in laboratory animals and experimental wounds
in humans [11]. Observational studies demonstrate that energy requirements are ele-
vated in patients with PUs [12]. Clinical trials also indicate that nutritional support
aids in the prevention and healing of PUs. Tables 1 and 2 describe controlled trials of
nutritional support in prevention and treatment of PUs.
Wound healing is impaired under considerable stressors, as indicated by studies
in laboratory animals and observational studies in patients [11]. Critical illness com-
pels the body to reprioritize macro- and micronutrients to combat infection and sus-
tain vital organs, often at the immediate expense of less- vital organs such as muscle
and skin. Competition for nutrients is exacerbated by inadequate nutritional intake.
These phenomena have extensive repercussions on nutrition and metabolic support
(as detailed elsewhere in this book). It is plausible that reprioritization hinders wound
healing, underscoring the importance of an adequate supply of energy, protein, and
micronutrients.
Unfortunately, the paucity of randomized controlled trials (RCTs) focusing on
ICU nutrition in the support of wound healing and the prevention of pathologic heal-
ing precludes formulation of evidence- based guidelines for clinicians. Nevertheless,
supplying ICU patients with at least the required quantities of calories, protein, and
micronutrients can be endorsed with sufficient certainty in order to prevent and treat
PUs. Immunonutrition may prove to be cost- effective in preventing PUs in high- risk
patients, and in treating existent ulcers.
Nutritional Support to Prevent and Treat Pressure Ulcers in the Intensive Care Unit
The paucity of clinical data precludes formulation of evidence- based recommenda-
tions for the nutritional approach to prevent and treat PUs in the ICU patient. In fact,
only a few high- quality studies have reported the impact of nutrition on PU burden in
other (non- ICU) settings. The largest study to date assessing the impact of nutritional
supplementation on the incidence of PU was a French multicenter, RCT conducted by
Bourdel- Marchasson et al. [13] on 672 elderly (age >65 years) inpatients without PUs
on admission. The impressive sample size and the inclusion only of patients (1) in the
acute phase of a serious illness that (2) could not feed themselves adequately render this
trial from 2000 pertinent to this chapter. All patients were assisted in eating the stan-
dard hospital diet that supplied 1,800 kcal. The intervention consisted of twice- daily
delivery of liquid oral supplements containing 200 kcal each (30% protein, 20% fat,
Nutrition Support for Wound Healing 183
50% carbohydrates) and micronutrients, including 1.8 mg zinc and 15 mg vitamin C.
The cumulative 15- day incidence of PUs was significantly lower in the nutritional
supplement group, even when accounting for various risk factors. This frequently
cited study provides evidence of nutritional supports potential to prevent PUs. It also
emphasizes the importance of multinutrient formulas, rather than pharmaconutrition
with a single nutrient implicated in wound healing. Although acutely ill (diagnoses
included CVA, heart failure, fractures), enrolled patients were hospitalized in geriatric
departments, not ICUs. Hence, the results are not completely valid for ICU patients
Table 1. Controlled trials of nutritional support in the prevention of PUs: prevention
Outcome(s)
1
Nutritional support Population
(sample size)
Author, year
controls intervention
incidence of PUs std. hospital diet std. hospital diet +
oral supplement
3
1/
day for 32 days
femoral neck fracture,
elderly
2
, (n = 59)
Delmi et al. [26], 1990
incidence of grade
24 PUs
5
std. hospital diet std. hospital diet +
1,000 ml overnight
enteral nutrition
4
for 2
weeks
femoral neck fracture,
risk of PU (n = 140)
Hartgrink [16], 1998
incidence of grade
14 PUs
std. hospital diet std. hospital diet +
oral supplement
7
for 2 weeks or until
discharge
elderly patients with
critical illness
6
(n = 672)
Bourdel- Marchasson et
al. [13], 2000
incidence of grade
1 or 2 PUs;
incidence of grade 2
PUs
std. hospital diet +
400 ml/day placebo
for 28 days or until
discharge
std. hospital diet +
400 ml/day oral
supplement
8
for 28
days or until discharge
femoral neck fracture
(n = 103)
Houwing et al. [27],
2003
incidence of grade
1-4 PUs
std. enteral nutrition immuno- enteral
nutrition
9
acute lung injury
(n = 100)
Theilla et al. [19], 2007
1
Statistically significant outcomes in nutritional intervention vs. control group.
2
Age >65 years.
3
254 kcal + micronutrients.
4
Trade name: Nutrison Steriflo Energy plus; 1,500 kcal and 60 gm protein (per liter).
5
Failure of intervention may be due to intolerance of overnight feeding.
6
See text for details.
7
200 kcal each (30% protein, 20% fat, 50% carbohydrates) and micronutrients, including 1.8 mg zinc and 15 mg vitamin C.
8
Trade name: Cubitan; contains 125 kcal/ml and micronutrients.
9
Trade name: Oxepa; contains protein, fat and carbohydrates; enriched in anti- inflammatory polyunsaturated fatty acids
(- linoleic, eicosapentaenoic and docosahexaenoic acids), antioxidant and prohealing vitamins (A, C, and E), and proheal-
ing micronutrients (Cu, Zn, and Mn).
184 Theilla
Table 2. Controlled trials of nutritional support in the treatment of PUs: intervention
Outcome(s)
1
Nutritional support Population
(sample size)
Author
(ref.), year
controls intervention
reduction in
PU surface area
placebo 2/day for 4
weeks
p.o. vitamin C, 500 mg 2/day
for 4 weeks
surgical patients with PUs
(n = 20)
Taylor et al.
[28], 1974
PU severity vitamin C, 10 mg 2/day
for 12 weeks
p.o. vitamin C, 500 mg 2/day
for 12 weeks
acute care and nursing
home elderly with PUs
(n = 88)
ter Riet et al.
[29], 1995
PU severity very- high- protein enteral
formula for 8 weeks
high- protein enteral formula
for 8 weeks
institutionalized, tube- fed
patients (n = 12)
Chernoff et al.
[15], 1990
reduction in
PU severity
(PUSH tool)
p.o. placebo p.o. collagen protein hydrolysate
supplement
2
3/day for
8 weeks
nursing home elderly with
PUs (n = 88)
Lee et al.
[18], 2006
reduction in
PU severity
(PUSH tool)
able to eat: std. hospital
diet;
tube fed: std. enteral
nutrition
able to eat: std. hospital diet +
400 ml/day oral supplement
3

for 12 weeks;
tube fed: 1,000 ml/day enhanced
enteral nutrition
4
+ std. enteral
nutrition for 12 weeks
institutionalized elderly
(n = 28)
Cereda et al.
[30], 2009
reduction in
PU surface area
std. hospital diet +
placebo
std. hospital diet + 200 ml 2/
day oral supplement
5
for
8 weeks
ambulatory,
institutionalized, and
hospitalized adults
(n = 43)
van Anholt et
al. [31], 2010
reduction in
PU severity
(PUSH tool)
regular enteral nutrition
formula
8
per REE
7
for
duration of ICU stay
enteral immunonutrition
6
per
REE for duration of ICU stay
patients in a general
ICU with stage IIIV PUs
(n = 40)
Theilla et al.
[20], 2012
reduction in
PU severity
(composite
score)
enteral formula at same
dose as before
enrollment
11
for
12 weeks
enteral formula
9
at BEE
10

1.31.5 for 12 weeks
tube- fed patients with
stage IIIIV PUs (n = 30)
Ohura et al.
[32], 2011
1
Statistically significant outcomes in nutritional intervention versus control group.
2
Trade name: Pro- Stat.
3
Trade name: Cubitan; contains 1.25 kcal/ml and micronutrients.
4
Trade name: Cubison; contains 1 kcal/ml, enriched in protein (20% energy), zinc, vitamin C, and arginine.
5
Trade name: Cubitan; contains 1.25 kcal/ml and micronutrients.
6
Trade name: Oxepa; contains protein, fat, and carbohydrates; enriched in anti- inflammatory polyunsaturated fatty acids
(- linoleic, eicosapentaenoic, and docosahexaenoic acids), antioxidant and prohealing vitamins (A, C, and E), and proheal-
ing micronutrients (Cu, Zn, and Mn).
7
Resting energy expenditure, as measured by IC.
8
Trade name: Jevity; contains protein, fat and carbohydrates, basal quantities of vitamins, and micronutrients.
9
Trade name: Rocal; contains protein, fat and carbohydrates, essential fatty acids (linoleic and - linolenic acids), vitamins,
copper, and zinc.
10
Basal energy expenditure (24- hour), calculated by the Harris- Benedict equation.
11
The daily energy prescription for the control group is not detailed in the article; however, the authors report that the
intervention group received significantly more energy and protein, on an absolute, per weight or per BEE basis.
Nutrition Support for Wound Healing 185
whose condition is usually more severe and are less capable of autonomous eating.
One may still surmise, although not based on evidence, that preventing nutritional and
energy deficits is even more crucial in the ICU than in acutely ill admitted to non- ICU
departments.
A Cochrane Collaboration report from 2003 systematically reviewed RCTs assessing
nutritional interventions to prevent or treat PUs in any setting [14]. In six of the eight
RCTs, nutritional support consisted of oral supplementations containing a mixture of
nutrients or of zinc, vitamin C, or protein alone. Only two studies assessed enteral
nutrition, provided to institutionalized [15] and hip fracture [16] patients. Trials were
heterogeneous and mostly of poor methodological quality, leading the reviewers to
decline from meta- analysis. The authors concluded that the evidence was insufficient
to make a case for or against a role for nutrition in PU management, but point out the
potential detected in the prevention study by Bourdel- Marchasson et al. [13].
A systematic review of intervention RCTs evaluating therapies for PUs was pub-
lished in the JAMA in 2008 [17]. As opposed to the Cochrane review, the JAMA arti-
cle evaluated numerous interventions, but included an analysis of studies assessing
the effect of nutritional supplementation on PU healing. The authors highlight one
RCT of high methodological quality that was published in the interim between the
reviews, in which Lee et al. [18] compared the effect of an oral nutritional supplement
based on hydrolyzed collagen protein to a placebo (n = 88). Oral protein supplemen-
tation enhanced healing of PUs in nursing home (long- term- care) patients, compared
to placebo. However, results were inconsistent in other RCTs, leading the JAMA
reviewers to conclude that . . . there is little evidence to support routine nutritional
supplementation . . .. Compared with standard care [17]. Between 2008 and the time
of preparing this manuscript, several other RCTs have been reported on the efficacy
of nutritional support in PU management, including studies assessing an enteral for-
mula in the prevention [19] and treatment [20] of PUs in the ICU. With the exception
of the aforementioned prevention study [19] (discussed below under immunonutri-
tion) studies assessing enteral nutrition in PUs had a small sample size. Thus, there is
a paucity of high- level evidence to guide nutritional management of PUs in the ICU.
Rather than equate lack of evidence with evidence of ineffectiveness, readers should
note that the JAMA review similarly reports on low evidence in support of other rou-
tinely implemented interventions to treat PUs, such as different support surfaces and
dressings, ultrasound, and vacuum therapy. Indeed, while acknowledging the imper-
fect state of evidence, the EPUAP and NPUAP still produced recommendations on
the prevention [5] and treatment [21] of PUs
1
, including nutritional support (dis-
cussed below). Furthermore, ICU patients with an expected hospitalization of more
than 4 days and with significantly reduced food intake deserve global nutritional sup-
port [22, 23] even in the absence of PUs or risk thereof.
1
These two references refer to the concise (and free for downloading) versions of both guidelines. The full
clinical practice guidelines are available for purchase through the NPUAP website at www.npuap.org.
186 Theilla
Protein and Energy Requirements
The EUPAP endorses the delivery of at least 30 35 kcal/kg/day and 1.25 1.5 g protein/kg
body to patients with or at risk of developing PU(s) in all healthcare settings [21]. In addi-
tion, the guidelines encourage consideration of nutritional support (enteral or parenteral
nutrition) when oral intake is inadequate, and to adjust the nutrition prescription accord-
ing to the individual patients overall condition. The panel considers the strength of evi-
dence in support of these recommendations to be C: recommendations were arrived at
by expert consensus, based on individual observational and experimental studies relating
protein and energy malnutrition to negative PU outcomes. Finally, the guidelines propose
to offer high- protein mixed oral nutritional supplements and/or tube feeding, in addi-
tion to the usual diet, to individuals with nutritional risk and PU risk because of acute or
chronic diseases, or following a surgical intervention (Strength of Evidence = A) [21].
Implementing the rule of thumb of 30 35 kcal/kg/day or more is likely to cover
the requirements of most patients, including those in the ICU. Indeed, observational
studies demonstrate that ICU patients are seldom administered this amount of calo-
ries, particularly in the initial days of hospitalization [22]. However, a recent invited
review on nutrition in the management of wound healing and PUs [24] conveyed the
importance of adjusting caloric requirements according to number, stage, and size of
PUs, as well as patient- specific factors such as age, comorbidities, etc., in order to avoid
under- or overfeeding. Of note, overfeeding and hyperglycemia may have a negative
impact on PU healing and other ICU outcomes. The reviewer cites indirect calorim-
etry (IC) as the ideal method to determine energy expenditure and requirements in
ICU patients in general, and advocates its use (when available) in patients with PUs
that fail to heal. The rationale behind employing IC, a time- and resource- consuming
practice, is that it integrates the various factors that influence energy expenditure,
including the demand incurred by PUs of various and fluctuating severity.
Recently, Cereda et al. [12] performed a systematic review and meta- analysis of stud-
ies in which resting energy expenditure was both measured (indirectly) and estimated
(per equation) in PU patients. The authors retrieved five studies fulfilling the predeter-
mined criteria three studies assessing paraplegic patients and two studies on the insti-
tutionalized/hospitalized elderly. Patients resting energy expenditure as determined
by IC was higher than that calculated using the Harris- Benedict equation (without a
factor) and higher than that measured in controls. Furthermore, PU patients accumu-
lated significant energy debt in all studies [12]. Although this meta- analysis included
only a small number of participants (101 controls, 92 patients) and did not focus on
ICU patients (due to absence of data), it does provide the highest level of evidence to
date for the (1) superiority of IC in determining energy requirements in patients with
PU, and (2) that PUs are associated with an elevated resting energy expenditure. In
short, delivering calories in the form of a mixed nutritional formula containing protein
and protein- sparing macronutrients and as determined by patients measured energy
expenditure is the ideal approach to managing coexisting critical illness and PUs.
Nutrition Support for Wound Healing 187
Micronutrients and Immunonutrition
Zinc, arginine, vitamin C, and vitamin A are essential for wound healing and sev-
eral (but not all) clinical trials demonstrated that delivering high doses of indi-
vidual nutrients was beneficial in the management of PUs. However, these trials
were methodologically flawed and nutrients were delivered as oral supplements to
non- ICU patients. The EUPAP emphasizes micronutrient intake in the prevention
and treatment of PUs, but does not specify quantities. Thus, at the present time,
complete enteral nutrition formulas are most appropriate to prevent PUs in the
ICU.
A relatively large RCT (n = 100) in a general ICU assessed the effect of an enteral
nutrition formula enriched with anti- inflammatory lipids (- linolenic, eicosapen-
taenoic, and docosahexaenoic acids); vitamins A, C, and E; zinc; manganese; and
copper on the development of PUs [19]. The formula was compared to adequate
basal enteral formulas and was delivered to intubated patients with acute lung injury
and no PUs at admission [25]. Importantly, all patients received ample energy and
protein, such that any benefit from the intervention could be attributed to micro-
nutrient enrichment. Indeed, the enhanced formula ameliorated acute lung injury
[25] and reduced the incidence of PUs, a secondary endpoint [19]. If replicated,
these findings would suggest that an increased risk for PUs may be an indication for
enteral immunonutrition in the acutely ill ICU patients. In a consequent RCT [20],
the authors examined the effect of the same formula on healing rates of PUs that
were present on or that developed during admission. Both treatment arms received
supplemental parental nutrition when indicated by ESPEN guidelines, though only
the intervention arm was administered fish oil- based emulsions. Healing rates (as
assessed by the PUSH tool) and CRP levels were significantly greater and lower,
respectively, in the intervention group. It may be that omega- 3 fatty acids (along
with other key micronutrients and in the context of adequate energy and protein)
enhance the transition from the inflammatory phase to the reparative- anabolic
phase of wound healing.
Conclusion
Pressure sores remain a significant source of morbidity and even mortality in
critically ill patients in the ICU. A review of the recent literature revealed interest-
ing and sometimes conflicting evidence regarding the prevention and healing of
PUs. Evidence suggests that a combination of enriched nutritional formulas which
include calories, protein, micronutirents, and omega- 3- polyunsaturated fatty acids
may have a role to play in the prevention of new ulcers and healing of existing
ulcers. It is clear that additional studies are required before clear recommendations
may be made.
188 Theilla
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3 Skipper A: Challenges in nutrition, pressure ulcers,
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BMJ 2006;332:472 475.
5 European Pressure Ulcer Advisory Panel and
National Pressure Ulcer Advisory Panel: Prevention
and Treatment of Pressure Ulcers: Quick Reference
Guide. Washington, National Pressure Ulcer
Advisory Panel, 2009. http://www.epuap.org/guide-
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Miriam Theilla, RN, Msc, PhD
Intensive Care Unit
Rabin Medical Center
IL 49100 Petah Tikva (Israel)
Tel. +972 543 979 457, E- Mail miriamt@clalit.org.il

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