Nutrition in Intensive Care Medicine Beyond Physiology

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 1–11

From Mitochondrial Disturbances to Energy RequirementsPierre Singer

Critical Care Medicine, Institute for Nutrition Research, Rabin Medical Center, Beilison Hospital,

Petah Tikva, Israel

AbstractAn 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 mechanism’s 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.

FADNADHNAD+

FADH2

Krebs

cycle

O2H2O

Matrix

Intermembrane

space

Mitochondrial membrane potential

Cyt CQ

I

II

VIVIII

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

CO2 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 VO2 % 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


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 Fio2 <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.

0

10

20

30

40

50

Co

ho

rts

(%)

19 to <

21

21 to <

23

23 to <

25

25 to <

27

27 to <

29

29 to <

31

31 to <

33

33 to <

35

35 to <

37

37 to <

39

39 to <

41

41 to <

43

43 to <

45

45 to <

47

47 to <

49

49 to <

51

51 to <

53

53 to <

55

55 to <

57

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.


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.


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 [email protected]




Protein Metabolism and RequirementsGianni Biolo

Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy

AbstractSkeletal 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 efflux

F Proteolysis

insulin resistance

Liver

F Gluconeogenesis

F Acute phase protein

F Urea synthesis

F Albumin synthesisIncreased 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


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 1.3–1.5 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 0.2–0.4 g/kg/day of

l- glutamine (e.g. 0.3–0.6 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 25–30% [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 10–15% 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].


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

intakeProtein

degradation

Protein synthesis

Oxidation

Urea

Free

amino acid

De novo synthesis

r

r nitric oxide synthesis

rrr

r

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.


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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 [email protected]




How to Choose the RouteIrina Grecu

Anaesthetics Department, University College Hospital, London, UK

AbstractChoosing 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 don’t use the gut, you’ll 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 metaanalysis 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


in patients with BMI <25 and ≥35 kg/m2. 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 metaanalysis 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 metaanalysis published in 2004 [29] found no

clinical benefit and recommended against routine parenteral supplementation to

enteral nutrition when the latter is insufficient. This metaanalysis 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


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 13 140

500

1,000

1,500

2,000

2,500

kca

l

Parenteral nutritionEnteral nutritionMeasured nutrition

a

1 2 3 4 5 6 7 8 9 10 11 12 13 140

500

1,000

1,500

2,000

2,500

kca

l

Parenteral nutritionEnteral nutritionCalculated targetMeasured energy expenditure

Daysb

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.


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: 1986–1995. Nutrition 1997;13:

870–877.

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


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 metaanalysis 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 gut’s 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):

S535–S540.

12 Levin RJ: Digestion and absorption of carbohy-

drates – from molecules and membranes to humans.

Am J Clin Nutr 1994;59:690S–698S.

13 Caspary WF: Physiology and pathophysiology of

intestinal absorption. Am J Clin Nutr 1992;55:

299S–308S.

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


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enteral feeding impairs intestinal carbohydrate

absorption in critically ill patients. Crit Care Med

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nutrition, provided within 24 h of injury or inten-

sive care unit admission, significantly reduces mor-

tality in critically ill patients: a metaanalysis of

randomised controlled trials. Intensive Care Med

2009;35:2018–2027.

16 McClave SA, Martindale RG, Vanek VW, et al:





Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter

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17 Villet S, Chiolero RL, Bollmann MD, et al: Negative



24:502– 509.


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ESPEN Guidelines on Parenteral Nutrition: inten-

sive care. Clin Nutr 2009;28:387– 400.

21 Miles JM: Energy expenditure in hospitalized

patients: implications for nutritional support. Mayo

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2009;35:1728– 1737.

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Am J Crit Care 2008;17:53– 61.

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:

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evidence- based feeding guidelines on mortality of

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26 Poulard F, Dimet J, Martin- Lefevre L, et al: Impact

of not measuring residual gastric volume in

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N Engl J Med 2011;365:506– 517.

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mizing enteral nutrition for critically ill patients – a

simple data- driven formula. Crit Care 2011;15:234.

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DK: Combination enteral and parenteral nutrition

in critically ill patients: harmful or beneficial? A

systematic review of the evidence. Intensive Care

Med 2004;30:1666– 1671.

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Control Study (TICACOS): a prospective, random-

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601– 609.

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(SPN) in intensive care unit (ICU) patients for opti-

mal energy coverage: improved clinical outcome.

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Irina Grecu, MD, PhD

Anaesthetics Department, University College Hospital

235 Euston Road, London NW1 2BU (UK)

E- Mail [email protected]




How to Prescribe Nutritional Support Using ComputersMette M. Berger

Service of Adult Intensive Care Medicine and Burns, Lausanne University Hospital, Lausanne, Switzerland

AbstractAs 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.


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 handheld 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 patient’s 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 patient’s

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 20–99 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 × VE + 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) + VE(31) + Tmax(167) – 6212

For patients with BMI ≥30 plus age ≥60 years:

2 REE = Mifflin(0.71) + VE(64) + Tmax(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; VE = minute ventilation (l/min); BSA = body

surface area.


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.


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

0.400.380.360.340.320.300.280.260.240.220.200.180.160.140.120.100.080.06

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.


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.

References


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20 Van den Berghe G, Schetz M, Vlasselaers D, et al:

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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 [email protected]




Oral FeedingAna Alvárez- Falcóna � Sergio Ruiz- Santanab

aDietetic Department and bIntensive Care Unit, Hospital Universitario de Gran Canaria Dr Negrín,

Las Palmas de Gran Canaria, Spain

AbstractEarly 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.


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 Alvárez- Falcón · 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


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 individual’s 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 individual’s 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


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



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 (14–15) 14 (9–15) < 0.001

SAPS II score, median (IQR) 33 (21–42) 40 (29–45) < 0.001

SOFA score, median (IQR) 2 (1–3) 5 (3–9) < 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 Negrín

ES– 35010 Las Palmas de Gran Canaria, Canary Islands (Spain)

Tel. +34 928 450673, E- Mail [email protected]




Enteral NutritionRonit Anbar

Institute for Nutrition Research and Nutrition Unit, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel

AbstractNutritional 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 metaanalysis 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 metaanalysis 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


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/

fluid 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 metaanalysis 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


28- day mortality rates [21– 23]. In a metaanalysis 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 patient’s 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 host’s 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 patient’s 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 patient’s 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


1 Kreymann KG, Berger MM, Deutz NEP: ESPEN

guidelines on enteral nutrition: intensive care. Clin

Nutr 2006;25:210–223.


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.


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 metaanalysis 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


mechanically ventilated, critically ill. JPEN J


8 Dickerson RN: Hypocaloric feeding of obese

patients in the intensive care unit. Curr Opin Clin

Nutr Metab Care 2005;8:189–196.

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






Parenteral NutritionRonan Thibaulta– c � Claude Pichardd

aClermont Université, Université d’Auvergne, Unité de Nutrition Humaine, bINRA, UMR 1019, UNH,

CRNH Auvergne, and cCHU Clermont- Ferrand, Service de Nutrition Clinique, Clermond- Ferrand, France; dNutrition Unit, Geneva University Hospital, Geneva, Switzerland

AbstractParenteral 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.


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 inflammation

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


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 24–48 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 = metaanalysis of randomized controlled trials, or at least 1 randomized controlled trial; B =

controlled, nonrandomized trials, or well- designed descriptive studies; C = expert opinions.


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


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


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’).


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

γ- 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, γ- 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 (100–200 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 PO4/day and from 80– 120


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, Chioléro 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;29:867–869.

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.


guidelines on enteral nutrition: intensive care. Clin

Nutr 2006;25:210–223.

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;27:355–373.

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 Wernicke’s encephalopathy is

achieved by high vitamin B1 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

Unité de Nutrition Hôpitaux Universitaires de Genève

Rue Gabrielle- Perret- Gentil, 4

CH– 1211 Genève 14 (Switzerland)


How Can Nutrition Interfere with Outcome?



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

AbstractMalnutrition, 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.


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


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 β- 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 CO2 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 insulin’s

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


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


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

20–25 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 1.2–1.5 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

20–25 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 1.2–1.5 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.


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 diff erent real-

life settings


2 Concurrent nutrition support modalities interact with the eff ect 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 eff ect 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


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


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.


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.

Benefit > risk

Monitoring

Fig. 1. Approach to optimal nutrition support in ACI to maximize benefits and minimize potential

risks.


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via the enteral route in critically ill patients: a single

center feasibility trial of the PEP uP protocol. Crit

Care 2010;14:R78.

41 Heyland DK, Cahill N, Day AG: Optimal amount

of calories for critically ill patients: depends on

how you slice the cake! Crit Care Med 2011;39:

2619–2626.



S, Madar Z: The tight calorie control study



patients. Intensive Care Med 2011;37:601–609.

Jeffrey I. Mechanick, MD

Division of Endocrinology, Diabetes, and Bone Diseases

Mount Sinai School of Medicine

1192 Park Avenue

New York, NY 10128 (USA)




Glucose ControlJean- Charles Preiser

Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium

AbstractStress- 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.


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.


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

180–200 180–200 180–200 140–180 180–200 180–200 140–180 ‘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 β- 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- α 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

1 Dungan KM, Braithwaite SS, Preiser JC: Stress

hyperglycaemia. Lancet 2009;373:1798– 1807.

2 Falciglia M, Freyberg RW, Almenoff PL, D’Alessio

DA, Render ML: Hyperglycemia- related mortality

in critically ill patients varies with admission diag-

nosis. Crit Care Med 2009;37:3001– 3009.

3 van den Berghe G, Wouters P, Weekers F, et al:

Intensive insulin therapy in the critically ill patients.

N Engl J Med 2001;345:1359– 1367.

4 van den Berghe G, Wilmer A, Hermans G, et al:

Intensive insulin therapy in the medical ICU. N Engl

J Med 2006;354:449– 461.

5 Arabi YM, Dabbagh OC, Tamim HM, et al: Intensive

versus conventional insulin therapy: a randomized

controlled trial in medical and surgical critically ill

patients. Crit Care Med 2008;36:3190– 3197.

6 Brunkhorst FM, Engel C, Bloos F, et al: Intensive

insulin therapy and pentastarch resuscitation in

severe sepsis. N Engl J Med 2008;358:125– 139.

7 De La Rosa GDC, Donado JH, Restrepo AH, et al:

Strict glycaemic control in patients hospitalised in a

mixed medical and surgical intensive care unit: a

randomised clinical trial. Crit Care 2008;12:R120.

8 Preiser JC, Devos P, Ruiz- Santana S, et al: A pro-

spective randomised multicentre controlled trial

on tight glucose control by intensive insulin therapy

in adult intensive care units: the Glucontrol study.


9 Finfer S, Chittock DR, Su SY, et al: Intensive versus

conventional glucose control in critically ill patients.

N Engl J Med 2009;360:1283– 1297.

10 Annane D, Cariou A, Maxime V, et al: Corticosteroid

treatment and intensive insulin therapy for septic

shock in adults: a randomized controlled trial.

JAMA 2010;303:341– 348.

11 Marik PE, Preiser JC: Toward understanding tight

glycemic control in the ICU: a systematic review

and metaanalysis. Chest 2010;137:544– 551.

12 Egi M, Bellomo R, Stachowski E, et al: Hypoglycemia

and outcome in critically ill patients. Mayo Clin

Proc 2010;85:217– 224.

13 Krinsley J, Schultz M, Spronk PE, et al: Mild hypo-

glycemia is independently associated with increased

mortality in the critically ill. Crit Care 2011;15:

R173.

14 Cheung NW, Napier B, Zaccaria C, Fletcher JP:

Hyperglycemia is associated with adverse outcomes

in patients receiving total parenteral nutrition.

Diabetes Care 2005;28:2367– 2371.

15 Casaer M, Mesotten D, Hermans G, et al: Early ver-

sus late parenteral nutrition in critically ill adults.

N Engl J Med 2011;365:506– 517.

16 Garber AJ, Moghissi ES, Bransome ED Jr, et al:

American College of Endocrinology position state-

ment on inpatient diabetes and metabolic control.

Endocr Pract 2004;10:77– 82.

17 Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle

P: Use of intensive insulin therapy for the manage-

ment of glycemic control in hospitalized patients: a

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College of Physicians. Ann Intern Med 2011;154:

260– 267.

18 Ichai C, Preiser JC, Société Française d’Anesthésie

Réanimation, Société de Réanimation de langue

Française: International recommendations for glu-

cose control in adult non diabetic critically ill


19 Krinsley JS, Preiser JC: Moving beyond tight glu-

cose control to safe effective glucose control. Crit

Care 2008;12:R149.

20 Schultz MJ, Harmsen RE, Spronk PE: Clinical

review: strict or loose glycemic control in critically

ill patients – implementing best available evidence

from randomized controlled trials. Crit Care 2010;

14:R223.

attention to maintaining BG at levels much lower than had previously been consid-

ered necessary. But the risks of tight glucose control then became apparent along with

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.

References

Glucose Control 89

21 Lena D, Kalfon P, Preiser JC, Ichai C: Glycemic

control in the intensive care unit and during the

postoperative period. Anesthesiology 2010;114:

438– 444.

22 Shepherd PR, Kahn BB: Glucose transporters and

insulin action – implications for insulin resistance

and diabetes mellitus. N Engl J Med 1999;341:

248– 257.

23 Li L, Messina JL: Acute insulin resistance following

injury. Trends Endocrinol Metab 2009;20:429– 435.

24 Thorell A, Nygren J, Ljungqvist O: Insulin resis-

tance: a marker of surgical stress. Curr Opin Clin

Nutr Metab Care 1999;2:69– 78.

25 Mowery NT, Dortch MJ, Dossett LA, et al: Insulin

resistance despite tight glucose control is associated

with mortality in critically ill surgical patients.

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26 Lacherade JC, Jacqueminet S, Preiser JC: An over-

view of hypoglycemia in the critically ill. J Diabetes

Sci Technol 2009;3:1242– 1249.

27 Oddo M, Schmidt JM, Carrera E, et al: Impact of

tight glycemic control on cerebral glucose metabo-

lism after severe brain injury: a microdialysis study.

Crit Care Med 2008;36:3233– 3238.

28 Ouattara A, Lecompte P, Le Manach Y, et al: Poor

intraoperative blood glucose control is associated

with a worsened hospital outcome after cardiac sur-

gery in diabetic patients. Anesthesiology 2005;103:

687– 694.

29 Egi M, Bellomo R, Stachowski E, French CJ, Hart G:

Variability of blood glucose concentration and

short- term mortality in critically ill patients.

Anesthesiology 2006;105:244– 252.

30 Ali NA, O’Brien JM Jr, Dungan K, et al: Glucose

variability and mortality in patients with sepsis. Crit

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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- [email protected]




GlutamineMike Kim � Paul E. Wischmeyer

Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colo., USA

AbstractGlutamine (GLN) has been shown to be a key pharmaconutrient in the body’s 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.


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 body’s 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 GLN’s 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- α 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- κB [21]. In mod-

els of experimental sepsis, our laboratory found that 0.75 g/kg of GLN can attenuate

nuclear binding/activation of NF- κB and prevent degradation of IκBα, its inhibitory

protein [21].

92 Kim · Wischmeyer

Data exist showing that GLN’s 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- κB following GLN treatment, nor do

they exhibit attenuation of TNF- α 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 α chain), CD45RO (leukocyte common antigen), and CD71 (transfer-

ring receptor) are dependent on the presence of GLN [22]. GLN is also required for

TNF- α 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 isocaloric/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 GLN’s 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 metaanalysis is available at http://

www.criticalcarenutrition.com). According to the results of the new metaanalysis

(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


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 body’s 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 metaanalysis 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 GLN’s 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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344– 357.

9 Wischmeyer PE: Glutamine and heat shock protein

expression. Nutrition 2002;18:225– 228.

10 Morrison AL, Dinges M, Singleton KD, Odoms K,

Wong HR, Wischmeyer PE: Glutamine’s protection

against cellular injury is dependent on heat shock

factor- 1. Am J Physiol Cell Physiol 2006;290:

C1625– C1632.

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12 Pelham HR: Speculations on the functions of the

major heat shock and glucose- regulated proteins.

Cell 1986;46:959– 961.

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PE: Effects of pharmaconutrients on cellular dys-

function and the microcirculation in critical illness.

Curr Opin Anaesthesiol 2009;22:177– 183.

14 Weiss YG, Bouwman A, Gehan B, Schears G, Raj N,

Deutschman CS: Cecal ligation and double punc-

ture impairs heat shock protein 70 (HSP- 70) expres-

sion in the lungs of rats. Shock 2000;13:19– 23.

15 Singleton KD, Serkova N, Beckey VE, Wischmeyer

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survival after sepsis: role of enhanced heat

shock protein expression. Crit Care Med 2005;33:

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16 Wischmeyer PE, Musch MW, Madonna MB, Thisted

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20 Chu EK, Ribeiro SP, Slutsky AS: Heat stress increases

survival rates in lipopolysaccharide- stimulated rats.

Crit Care Med 1997;25:1727– 1732.

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2008;138:2025S– 2031S.

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the French controlled, randomized, double- blind,

multicenter study. Crit Care Med 2006;34:598– 604.

24 Bakalar B, Duska F, Pachl J, et al: Parenterally

administered dipeptide alanyl- glutamine prevents

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25 Novak F, Heyland DK, Avenell A, Drover JW, Su X:

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2002;30:2022– 2029.

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trial of glutamine, selenium, or both, to supplement

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centre randomised clinical trial of intensive care

unit patients. Acta Anaesthesiol Scand 2011;55:812–

818.

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L- alanyl- L- glutamine dipeptide supplemented total

parenteral nutrition on infectious morbidity and

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Med 2011;39:1263– 1268.

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and alanine on severe traumatic brain injury. Clin J

Traumatol 2007:145– 149.

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glutamine supplementation to head trauma patients

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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)





Leucine and Citrulline: Two Major Regulators of Protein TurnoverLuc Cynobera,b � Jean- Pascal de Bandta,b � Christophe Moinardb

aClinical Chemistry Laboratory, Cochin and Hotel- Dieu Hospitals, AP- HP, and bDepartment of Experimental,

Metabolic and Clinical Biology, EA 4466, Paris Descartes University, Paris, France

AbstractBoth 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.


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

CH2CH3

CH3

CHCOOH

CH

Leucine

�-Methylpropionyl-CoA

Valine Isoleucine

�-Methyl butanoyl-CoA

CH3

CH3

CHNH2

COOHCH

NH2 C2H5

CH3

C2H5

CH3

CHNH2

COOHCH

CHCH2CH

CH3

CH3

CH COOHC

O

CH COOHC

O

C2H5

CH3

CH

O

CH2CH3

CH3

CH3

CH3

CH3

CH3

CH COOHC

O

CoAC ~ S CoAC ~ S CoAC ~ S

O OIsovaleryl-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, α- 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 β- 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


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


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, Iresjö 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

1.4/0.8/1a 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.


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


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. Poincaré 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 Plénier 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


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6 Malaisse WJ: Branched- chain amino and keto acid

metabolism in pancreatic islets. Adv Enzyme Regul

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7 De Bandt JP, Cynober L: Therapeutic use of

branched- chain amino acids in burn, trauma, and

sepsis. J Nutr 2006;136(Suppl):308S– 313S.

8 Vary TC: Acute oral leucine administration stimu-

lates protein synthesis during chronic sepsis through

enhanced association of eukaryotic initiation factor

4G with eukaryotic initiation factor 4E in rats.

J Nutr 2007;137:2074– 2079.

9 Lang CH, Frost RA, Bronson SK, Lynch CJ, Vary

TC: Skeletal muscle protein balance in mTOR

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leucine. Am J Physiol Endocrinol Metab 2010;298:

E1283– E1294.

10 Biolo G, De Cicco M, Dal Mas V, Lorenzon S,

Antonione R, Ciocchi B, et al: Response of muscle

protein and glutamine kinetics to branched- chain-

enriched amino acids in intensive care patients after

radical cancer surgery. Nutrition 2006;22:475– 482.

11 Sun LC, Shih YL, Lu CY, Hsieh JS, Chuang JF, Chen

FM, Ma CJ, Wang JY: Randomized, controlled study

of branched chain amino acid- enriched total paren-

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2008;74:237– 242.

12 Tomiya T, Inoue Y, Yanase M, Arai M, Ikeda H,

Tejima K, et al: Treatment with leucine stimulates

the production of hepatocyte growth factor in vivo.

Biochem Biophys Res Commun 2004;322:772– 777.

13 Fan ST, Lo CM, Lai EC, Chu KM, Liu CL, Wong J:

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going hepatectomy for hepatocellular carcinoma.

N Engl J Med 1994;331:1547– 1552.

14 Okabayashi T, Nishimori I, Sugimoto T, Maeda H,

Dabanaka K, Onishi S, et al: Effects of branched-

chain amino acids- enriched nutrient support for

patients undergoing liver resection for hepatocellu-

lar carcinoma. J Gastroenterol Hepatol 2008;23:

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15 Okabayashi T, Nishimori I, Yamashita K, Sugimoto

T, Namikawa T, Maeda H, Yatabe T, Hanazaki K:

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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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Shinoura S, Umeda Y, Sato D, Utsumi M, Nagasaka

T, Okazaki N, Date A, Noguchi A, Tanaka A,

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post- transplant period after living donor liver trans-

plantation. J Hepatobiliary Pancreat Sci 2012;19:

438– 448.

18 Shirabe K, Yoshimatsu M, Motomura T, Takeishi K,

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Lundholm K: Appearance of individual amino acid

concentrations in arterial blood during steady- state

infusions of different amino acid formulations to

ICU patients in support of whole- body protein

metabolism. JPEN J Parenter Enteral Nutr 2006;30:

277– 285.

20 Bérard MP, Pelletier A, Ollivier JM, Gentil B,

Cynober L: Qualitative manipulation of amino acid

supply during parenteral nutrition in surgical

patients. JPEN J Parenter Enteral Nutr 2002;26:

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acids in altered nutrition. Metabolism 1976;25:

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diminished de novo arginine and nitric oxide pro-

duction. Am J Clin Nutr 2009;89:142– 152.

24 Crenn P, Hanachi M, Neveux N, Cynober L: La cit-

rullinémie: un biomarqueur de la fonctionnalité

intestinale. Ann Biol Clin 2011;69:513– 521.

25 van Waardenburg DA, de Betue CT, Luiking YC,

Engel M, Deutz NEP: Plasma arginine and citrulline

concentrations in critically ill children: strong rela-

tion with inflammation. Am J Clin Nutr 2007;86:

1438– 1444.

26 Piton G, Manzon C, Monnet E, Cypriani B, Barbot

O, Navellou JC, et al: Plasma citrulline kinetics and

prognostic value in critically ill patients. Intensive

Care Med 2010;36:702– 706.

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Capellier G: Acute intestinal failure in critically ill

patients: is plasma citrulline the right marker?


28 Haines RJ, Pendleton LC, Eichler DC: Arginin-

osuccinate synthase: at the center of arginine metab-

olism. Int J Biochem Mol Biol 2011;2:8– 23.

29 Faure C, Raynaud- Simon A, Ferry A, Daugé V,

Cynober L, Aussel C, Moinard C: Effects of citrul-

line and leucine on muscle function in malnour-

ished aged rats. Amino Acids 2012;42:1425–1433.

30 Le Plénier S, Walrand S, Noirt R, Cynober L,

Moinard C: Effects of leucine and citrulline versus

nonessential amino acids on muscle protein syn-

thesis in fasted rat: a common activation pathway?

Amino Acids 2012, E- pub ahead of print.

31 Batista MA, Nicoli JR, Martins Fdos S, Machado JA,

Arantes RM, Quirino IE, Correia MI, Cardoso VN:

Pretreatment with citrulline improves gut barrier

after intestinal obstruction in mice. JPEN J Parenter

Enteral Nutr 2012;36:69– 76.

32 Grisafi D, Tassone E, Dedja A, Oselladore B, Masola

V, Guzzardo V, Porzionato A, Salmaso R, Albertin

G, Artusi C, Zaninotto M, Onisto M, Milan A,

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hiandetti L, Filippone M, Zaramella P: L: - citrulline

prevents alveolar and vascular derangement in a rat

model of moderate hyperoxia- induced lung injury.

Lung 2012;190:419– 430.

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, Hôpital Cochin

27 rue du Faubourg- Saint- Jacques

FR– 75014 Paris (France)

Tel. +33 0 1 58 41 15 91, E- Mail [email protected]

Organ- Targeted Nutrition



The Surgical/Trauma PatientArved Weimann

Klinik für Allgemein- und Visceralchirurgie, Klinikum St. Georg gGmbH Leipzig, Leipzig, Germany

AbstractIn 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 defi ciency 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].


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 metaanalysis

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.


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

metaanalysis [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, γ- 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


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,

Krähenbühl 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, Küchenhoff 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 metaanalysis 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 metaanalysis [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.

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33 Peterson SJ, Tsai AA, Scala CM, Sowa DC, Sheehan



Diet Assoc 2010;110:427– 433.

Prof. Dr. Arved Weimann, MA

Klinik für Allgemein-und Visceralchirurgie, Klinikum St. Georg gGmbH Leipzig

Delitzscher Strasse 141

DE– 04129 Leipzig (Germany)





Nutrition and SepsisJonathan Cohena,b � W. Dat N. Chinc

aThe Department of General Intensive Care, Rabin Medical Center, Campus Beilinson, Petah Tikva, and bThe Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; cDivision of Critical Care Medicine,

University of Alberta, Edmonton, Alta., Canada

AbstractThe 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.


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- α 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 metaanalysis 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 naïve CD4 helper lymphocytes by

exposure to bacterial antigens; invokes immune response

of tolerance

Naïve CD4 helper lymphocytes proliferate along the

Th1 pathway generating proinflammatory effects


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 metaanalysis, 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 metaanalysis 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- α, IL- 1β, 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- κB, 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].


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, γ- 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, γ- linolenic acid, and antioxidants, 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


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:

461–482.

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 metaanalysis of randomized controlled trials.

Intensive Care Med 2009;35:2018–2027.

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 fi sh oil, probiotics, or

antioxidants positively aff ects outcome in patients with established sepsis.

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Prof. Jonathan Cohen

Department of General Intensive Care, Rabin Medical Center

Campus Beilinson






The Renal Failure PatientWilfred Druml

Department of Medicine III, Division of Nephrology, Medical University of Vienna, Vienna, Austria

AbstractRenal 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.


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 activationOther endocrine abnormalities: hyperparathyroidism, erythropoietin resistance,

resistance to growth factors, etc.


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- α, 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 organism’s 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


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 B6, 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- α, 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 20–30 (max. 35) kcal/kg/day

Glucose 3–5 g/kg/day

Lipids 0.8–1.2 (max. 1.5) g/kg/day

Amino acids/protein

Conservative therapy 0.8–1.2 g/kg/day

+ RRT 1.3–1.5 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.


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


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


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.



N Engl J Med 2011;365:506– 517.

Wilfred Druml, MD

Klinik für Innere Medizin III, Abteilung für Nephrologie

Währinger Gürtel 18– 20

AT– 1090 Vienna (Austria)





n- 3 Fatty Acids and γ- Linolenic Acid Supplementation in the Nutritional Support of Ventilated Patients with Acute Lung Injury or Acute Respiratory Distress SyndromeShaul 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

AbstractAcute 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, γ- 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 γ- 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 (Pao2:Fio2 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 inflammatory 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

inflammatory mediators, decreased neutrophil invasion, and reduced protein influx

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 fish 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 O2 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 E1. 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, γ- 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, β- 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.


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 Pao2:Fio2 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 metaanalysis 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 significant).

In this study no improvement in the gas exchange measured by the Pao2/Fio2 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 B4 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.


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 Pao2/Fio2 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:

533–545.



versus full- energy enteral nutrition in mechanical


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;335:389–394.

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:

12–17.

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;27:1409–1420.

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 metaanalysis 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 antioxidants 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


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.







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


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




Tel. + 972 3 9376521, E- Mail [email protected]




ObesityDavid C. Frankenfield

Department of Clinical Nutrition and Department of Nursing, Penn State Milton S. Hershey Medical Center,

Hershey, Pa., USA

AbstractObesity 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.


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 fi rst 152 cm of height plus 1.07 kg for each additional cm of

height

2 Women: 45 kg for the fi rst 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 (Frankenfield)

Ca

lcu

late

d R

MR

(k

cal/

da

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

3,000Linear: 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 40±16 NA 1 57±21 NA

2 41±13 NA 2 57±17 NA

3 39±8 NA 3 58±14 NA

Height, cm 1 170±10 NA 1 170±9 NA

2 170±11 NA 2 172±11 NA

3 169±11 NA 3 170±11 NA

Weight, kg 1 69±12 1.00 1 74±11 1.00

2 99±17 1.42 2 103±15 1.39

3 152±43 2.19 3 142±42 1.92

BMI 1 24.0±2.8 1.00 1 25.3±2.6 1.00

2 33.9±3.2 1.42 2 34.3±2.6 1.36

3 52.7±10.9 2.19 3 49.1±13.2 1.94

RMR, kcal/day 1 1471±254 1.00 1 1824±400 1.00

2 1801±391 1.23 2 2202±482 1.20

3 2386±521 1.62 3 2361±493 1.29

RMR, % Mifflin 1 1.01±0.08 1.00 1 1.25±0.17 1.00

2 1.03±0.13 1.02 2 1.26±0.16 1.01

3 1.04±0.09 1.03 3 1.14±0.16 0.91

RMR, kcal/wt 1 21±2 1.00 1 25±4 1.00

2 18±3 0.86 2 21±3 0.87

3 16±2 0.74 3 17±3 0.69

RMR, kcal/IBW 1 21±2 1.00 1 25±4 1.00

2 28±5 1.33 2 32±4 1.28

3 38±5 1.01 3 36±6 1.44

RMR, kcal/MAW 1 21±2 1.00 1 25±4 1.00

2 25±4 1.12 2 29±4 1.16

3 28±3 1.27 3 28±4 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 (Vco2). 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

Vco2 may be of benefit in the care of obese patients in the critical care unit, but com-

pared to the Vco2 associated with overall energy demands, the added carbon diox-

ide related to feeding is minor, accounting for 13% of the total Vco2 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 Vco2 associated with overfeeding, the overall Vco2

was lower in the overfed obese patients (263 ± 42 ml/min vs. 279 ± 60 ml/min) and

neither the Paco2 (39.2 ± 6.3 vs. 38.2 ± 6.3 torr) nor the ratio of minute ventilation to

Vco2 (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

Ob

ese

ov

erf

ed

No

no

be

se u

nd

erf

ed

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 600500

CO

2 p

rod

uct

ion

(m

l/m

in)

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 VCO2 = 12.3 + 0.760 VO2 + 0.863 total kcal intake/kg metaboli-

cally active weight (R2 0.92). Closed circles are obese patients, open circles are nonobese patients.

Broken lines represent the differences in VCO2 in obese underfed and overfed patients across the

range of VO2 using the mean caloric intake to compute the VCO2 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 20.0–29.9

n = 101

BMI 30.0–40.0

n = 66

BMI >40.0

n = 34

±10%1 >–10%2 >+10%3 range4 +10%1 >–10%2 >+10%3 range4 +10%1 >–10%2 >+10%3 range4

ACCPwt 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

ACCPMAW – – – – 0.38 0.58 0.04 –31 to 18 0.59 0.38 0.03 –32 to 17

ACCPIBW – – – – 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


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 Müller 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 Dickerson’s study was very close to being within

the 25– 35 segment in which Alberda could find no advantage to reaching energy bal-

ance, while Dickerson’s 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.

References

Obesity 153

6 Frankenfield DC, Ashcraft CM: Estimating energy

needs in nutrition support patients. JPEN J Parenter

Enteral Nutr 2011;35:563– 570.

7 Frankenfield DC, Smith JS, Cooney RN, Blosser SA:

Relative association of fever and injury with hyper-

metabolism in critically ill patients. Injury 1997;28:

617– 621.

8 Frankenfield DC, Rowe WA, Smith JS, Cooney RN:

Validation of several established equations for rest-

ing metabolic rate in obese and nonobese people.

J Am Diet Assoc 2003;103:1152– 1159.

9 Mifflin MD, St Jeor ST, Hill LA, Scott BJ, Daugherty

SA, Koh YO: A new predictive equation for resting

energy expenditure in healthy individuals. Am J

Clin Nutr 1990;51:241– 247.

10 Weijs PMJ: Validity of predictive equations for rest-

ing energy expenditure in US and Dutch obese class

I and class II adults aged 18– 65 y. Am J Clin Nutr

2008;88:959– 970.

11 Kress JP, Pohlman AS, Alverdy J, Hall JA: The impact

of morbid obesity on oxygen cost of breathing at

rest. Am J Respir Crit Care Med 1999;160:883– 886.

12 Frankenfield DC, Rowe WA, Cooney RC, Smith JS,

Becker D: Limits of body mass index to detect obe-

sity and predict body composition. Nutrition 2001;

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13 McClave SA, Kushner R, Van Way CW, et al:



dations. JPEN J Parenter Enteral Nutr 2011;35:

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14 Dickerson RN, Boschert KJ, Kudsk KA, Brown RO:

Hypocaloric enteral tube feeding in critically ill

obese patients. Nutr 2002;18:241– 246.

15 Dickerson RN, Rosato EF, Mullen JL: Net protein

anabolism with hypocaloric parenteral nutrition in

obese stressed patients. Am J Clin Nutr 1986;44:

747– 755.

16 Choban PS, Burge JC, Scales D, Flancbaum L:

Hypoenergetic nutrition support in hospitalized

obese patients: a simplified method for clinical

application. Am J Clin Nutr 1997;66:546– 550.

17 Frankenfield DC, Smith JS, Cooney RN: Accelerated

nitrogen loss after traumatic injury is not attenuated

by achievement of energy balance. JPEN J Parenter

Enteral Nutr 1997;21:324– 329.

18 Porhomayon J, Papadakos P, Singh A, Nader ND:

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anesthesia- critical care physician. HSR Proc

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19 Long CL, Birkhahn RH, Geiger JW, et al: Urinary

excretion of 3- methylhistidine: an assessment of

muscle protein catabolism in adult normal subjects

during malnutrition, sepsis, and skeletal trauma.

Metabolism 1981;30:765– 776.

20 Cerra FB, Benitez MR, Blackburn GK, Irwin RS,

Jeejeebhoy K, Katz DP, Pingleton SK, Pomposelli J,

Rombeau JL, Shronts E, Wolfe RR, Zaloga GP:

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21 Frankenfield DC, Schubert A, Alam S, Cooney RN:

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mechanically ventilated patients. Am J Clin Nutr

2003;78:241– 249.





Clin Nutr 2011;1:2– 3.

25 Weijs PJM, Stapel SN, de Groot SDW, Driessen RH,

de Jong E, Girbes ARJ, Strack van Schijndel RJN,

Beishuizen A: Optimal protein and energy nutrition

decreases mortality in mechanically ventilated, crit-

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study. JPEN J Parenter Enteral Nutr 2012;36:60– 68.

26 Singer P, Anbar R, Cohen J, Shapiro H, Salita-

Chesner M, Lev S, Grozouski E, Theilla M, Frishman

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2009;35:1728– 1737.

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)





Nutritional Imbalances during Extracorporeal Life SupportIlya Kagan � Pierre Singer

General Intensive Care Department and Institute for Nutrition Research, Rabin Medical Center,

Beilinson Hospital, Petah Tikva, Israel

AbstractExtracorporeal 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. 126–135]). 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 patient’s 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 CO2 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 (1–1.5 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 0.2–0.3 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


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 (Vo2) and carbon dioxide production (Vco2), as well

as minute volume [15]. CO2 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 10–20 g amino acid/day, depending on RTT modality and filter type 10–15% of

infused amino acids are lost with CRRT

Glutamine Loss up to 10–15% (0.5–6.8 g) with CVVH when supplementation level is 0.32 g/kg/day

Vitamin C Up to 600 μmol/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;32:958–963.

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;11:293–299.

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;24:169–175.

10 Berger MM, Shenkin A, Revelly JP, Roberts E,

Cayeux MC, Baines M, Chioléro RL: Copper, sele-

nium, zinc, and thiamine balances during continu-

ous venovenous hemodiafiltration in critically ill

patients. Am J Clin Nutr 2004;80:410–416.

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:

196–200.

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:e1–e9.

13 Chan LN: Nutritional support in acute renal failure.

Curr Opin Clin Nut Metab Care 2004;7:207–212.

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


2003;19:909–916.

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;27:220–223.

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


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 Lukas G, Davies AR, Hilton AK, Pellegrino VA,

Scheinkestel CD, Ridley E: Nutritional support in

adult patients receiving extracorporeal membrane

oxygenation. Crit Care Resusc 2010;12:230–234.

21 Scott LK, Boudreaxus K, Thaljeh F, Grier LR,

Conrad SA: Early enteral feedings in adults receiv-

ing venovenous extracorporal membrane oxygen-

ation. JPEN J Parenter Enteral Nutr 2004;28:

295– 300.

22 Revelly JP, Tappy L, Berger MM, Gersbach P, Cayeux

C, Chiolero R: Metabolic, systemic and splanchnic

hemodynamic responses to early enteral nutrition

in postoperative patients treated for circulatory

compromise. Intensive Care Med 2001;27:540– 547.

Ilya Kagan, MD

General Intensive Care Department and Institute for Nutrition Research







Nutrition in PancreatitisStephen A. McClave

Department of Medicine, University of Louisville School of Medicine, Louisville, Ky., USA

AbstractSevere 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 patient’s hospital course in a favorable manner.


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 metaanalysis 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 metaanalysis 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


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

Ranson’s 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 8–12 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


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 patient’s wishes were a better indicator of successful

advancement [27]. In fact, using the patient’s 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 body’s 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


1 McClave SA, Chang WK, Dhaliwal R, Heyland DK:

Nutrition support in acute pancreatitis: a systematic

review of the literature. JPEN J Parenter Enteral

Nutr 2006;302:143– 156.

2 Jafri NS, Mahid SS, Gopathi SK, Hornung CA,

Galandiuk S, McClave SA: Enteral nutrition is supe-

rior to total parenteral nutrition in severe acute

pancreatitis: a systematic review and metaanalysis.

Gastro 2008;Vol:A- 141.

3 Petrov MS, Pylypchuk RD, Uchugina AF: A system-

atic review on the timing of artificial nutrition in

acute pancreatitis. Br J Nutr 2009;101:787– 793.

4 Mirtallo J, Forbes A, McClave SA, Jensen GI:

International Consensus Guidelines for Nutrition

Therapy in Pancreatitis. JPEN J Parenter Enteral

Nutr 2012;36:284– 291.

5 Forsmark CE, Baillie J, AGA Institute Clinical

Practice and Economics Committee, AGA Institute

Governing Board: AGA Institute technical review

on acute pancreatitis. Gastroenterology 2007;132:

2022– 2044.

6 Davies AR, Morrison SS, Ridley EJ, Bailey M, Banks

MD, Cooper DJ, Hardy G, McIlroy K, Thomson A,

ASAP Study Investigators: Nutritional therapy in

patients with acute pancreatitis requiring critical

care unit management: a prospective observational

study in Australia and New Zealand. Crit Care Med

2011;39:462– 468.

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,

Atlanta, Ga, September 11 through 13, 1992. Arch

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13 Marik PE, Zaloga GP: Gastric versus postpyloric

feeding: a systematic review. Crit Care 2003;7:

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bolster the body’s 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 B12 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

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14 Eatock FC, Chong P, Menezes N, Murray L, McKay

CJ, Carter CR, et al: A randomized study of early

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15 Kumar A, Singh N, Prakash S, et al: Early enteral

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17 Park KS, Lim JW, Kim H: Inhibitory mechanism of

omega- 3 fatty acids in pancreatic inflammation and

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S: Randomized clinical trial of specific lactobacillus

and fibre supplement to early enteral nutrition in

patients with acute pancreatitis. Br J Surg 2002;89:

1103– 1107.

19 Oláh A, Belágyi T, Pótó L, Romics L Jr, Bengmark S:

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severe acute pancreatitis: a prospective, random-

ized, double blind study. Hepatogastroenterology

2007;54:590– 594.

20 Besselink MG, van Santvoort JC, Buskens E, et al:

Probiotic prophylaxis in predicted severe acute pan-

creatitis: a randomised, double- blind, placebo-

controlled trial. Lancet 2008;371:651– 659.

21 McClave SA, Martindale RG, Vanek VW, McCarthy


Cresci G: Guidelines for the Provision and

Assessment of Nutrition Support Therapy in the

Adult Critically Ill Patient: Society of Critical Care

Medicine (SCCM) and the American Society for

Parenteral and Enteral Nutrition (ASPEN). JPEN J


22 Sharma B, Srivastava S, Singh N, Sachdev V, Kapur

S, Saraya A: Role of probiotics on gut permeability

and endotoxemia in patients with acute pancreati-

tis: a double- blind randomized controlled trial.

J Clin Gastroenterol 2011;45:442– 448.

23 Sax HC, Warner BW, Talamini MA: Early total par-

enteral nutrition in acute pancreatitis: lack of bene-

ficial effects. Am J Surg 1987;153:117– 124.

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 Lévy 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

prospective study of 116 patients. Gut 1997;40:

262– 266.

26 Sathiaraj E, Murthy S, Mansard MJ, Rao GV,

Mahukar S, Reddy DN: Clinical trial: oral feeding

with a soft diet compared with clear liquid diet as

initial meal in mild acute pancreatitis. Aliment

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.

28 Wilson C, Heath DI, Imrie CW: Prediction of out-

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-

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Stephen A. McClave, MD, Professor of Medicine

Division of Gastroenterology, Hepatology and Nutrition

University of Louisville School of Medicine

Louisville, KY 40202 (USA)





Which Nutritional Regimen for the Comorbid Complex Intensive Care Unit Patient?Pierre Singera � Hadas Weinbergerb � Boaz Tadmora

aRabin Medical Center, Beilinson Hospital, Petah Tikva, and bHolon Institute of Technology, Holon, Israel

AbstractIntensive 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.


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. 69–81], 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

11–14 kcal/kg ABW

22–25 kcal/kg IBW

2.0–2.5 g/kg high fiber,

low carbohydrate load

Elderly sarcopenia IC

20–25 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

25–30 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.


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 γ- 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).


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

OPatient

Fig. 1. Comorbidities.


the multicriteria decision- making situation. Ambiguity, amongst other decision ele-

ments, might consequently provoke discrepancy between a physician’s 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 physician’s

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

Energy

Risks

Agents

Fig. 2. Ontology of comorbidity conditions and nutritional implications.


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 physician’s 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).


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 Defi ning 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 Identifi cation of personalized best practices towards patient reaction and drug

utilization with relation to micro- and macronutrients support

4 Defi ne 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 • • •


1 Christiansen CF, Christensen S, Johansen MB,

Larsen KM, Tonnesen E, Sorensen HT: The impact

of preadmission 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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Tel. +972 3 9376521, E-Mail [email protected]




Nutrition Support for Wound Healing in the Intensive Care Unit PatientMiriam Theilla

Intensive Care Unit, Rabin Medical Center, Petah Tikva, Israel

AbstractThe 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- à- 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

Energy,

protein, and

micronutrient

requirements

Energy,

protein, and

micronutrient

supply

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 skin’s 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,


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 support’s 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 supplement3 ×1/

day for 32 days

femoral neck fracture,

elderly2, (n = 59)

Delmi et al. [26], 1990

↔ incidence of grade

2–4 PUs5

std. hospital diet std. hospital diet +

1,000 ml overnight

enteral nutrition4 for 2

weeks

femoral neck fracture,

↑ risk of PU (n = 140)

Hartgrink [16], 1998

↓ incidence of grade

1–4 PUs

std. hospital diet std. hospital diet +

oral supplement7

for 2 weeks or until

discharge

elderly patients with

‘critical’ illness6

(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


400 ml/day oral

supplement8 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

nutrition9

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

(γ- 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.), yearcontrols 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

supplement2 × 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 supplement3

for 12 weeks;

tube fed: 1,000 ml/day enhanced

enteral nutrition4 + std. enteral

nutrition for 12 weeks

institutionalized elderly

(n = 28)

Cereda et al.

[30], 2009

↑ reduction in

PU surface area


placebo

std. hospital diet + 200 ml × 2/

day oral supplement5 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

formula8 per REE7 for

duration of ICU stay

enteral immunonutrition6 per

REE for duration of ICU stay

patients in a general

ICU with stage II–IV 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 formula9 at BEE10 ×

1.3–1.5 for 12 weeks

tube- fed patients with

stage III–IV 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

(γ- 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 α- 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.


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 metaanalysis. 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 PUs1, 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 patient’s 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 metaanalysis 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 metaanalysis 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.


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 (γ- 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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Miriam Theilla, RN, Msc, PhD

Intensive Care Unit

Rabin Medical Center



Nutrition in Intensive Care Medicine Beyond Physiology

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