117610880 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 111

From Mitochondrial Disturbances to Energy RequirementsPierre SingerCritical 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 mechanisms modeling nutrient administration with acute illness. Copyright 2013 S. Karger AG, Basel

An organism is very sensitive to variations in the intake of nutrients. Excess substrate increases oxidative processes, inducing reactive oxygen species and creating messages to the endothelial reticulum stimulating inflammatory pathways. Nutritional excesses in the critically ill may increase the oxidative load and alter immune function. In contrast, hypocaloric regimens may decrease oxidative stress in a comparable way to metabolic syndrome and so decrease the production of reactive oxidative tissues. Recently, the debate concerning how many calories to administer to a critically ill patient has moved from how much to other aspects such as by which route or early versus late, increasing confusion in the debate [1]. Definitively, mitochondria are at the center of the problem, being able to react to any deficit or excess in energy and regulating ATP production. Mitochondrial oxidative phosphorylation is responsible for over 90% of total oxygen consumption and ATP generation [2]. Four individual enzyme complexes (I IV) are generated by the mitochondria and can be inhibited by

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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

Krebscycle

O2H2O

Matrix

Intermembranespace

Mitochondrial membrane potential

Cyt CQ

I

II

VIVIII

e e

e

e

H+ H+ H+ H+H+

H+

ADP + PiATP

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 2,257Oxygen consumption, l/g 0.747 2.013 1.045CO2 production, l/g 0.747 1.4 0.864RQ 1.00 0.70 0.83Energy potential, kcal/g 3.87 9.69 4.70ATP synthesized, kcal/mol 456 1548 450

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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 2.5Brain 20 2.0Heart 10 0.5Kidneys 10 0.5Muscles 20 40Other 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 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

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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


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

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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.

References

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9 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.

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11 McClave SA, Marindale RG, Vanek VW, et al: Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). JPEN J Parenter Enteral Nutr 2009;33:277 316.

12 Boullata J, Williams J, Cottrell F, Hudson L, Compher C: Accurate determination of energy needs in hospitalized patients. Am J Diet Assoc 2007;107:393 401.

13 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;26:1 9.

14 Reid C: Frequency of under- and overfeeding in mechanically ventilated ICU patients: causes and pos-sible consequences. J Hum Nutr Diet 2006;19:13 22.

15 Kreymann KG, DeLegge MH, Luft G, Hise ME, Zaloga G: The ratio of energy expenditure to nitro-gen loss in diverse patient groups: systematic review. Clin Nutr 2012;31:168 175.

16 Kyle U, Genton L, Heiddeger CP, et al: Hospitalized mechanically ventilated patients are at higher risk of enteral underfeeding than non- ventilated patients. Clin Nutr 2006;25:727 735.

17 Peterson SJ, Tsai AA, Scala CM, Sowa DC, Sheean PM, Braunschweig CL: Adequacy of oral intake in critically ill patients 1 week after extubation. J Am Diet Assoc 2010;110:427 433.

18 Higgins PA, Daly BJ, Lipson AR, Guo SR: Assessing nutritional status in chronically critically ill adult patients. Am J Critical Care 2006;15:166 177.

19 Papirov G, Vovovotz L, Zeidenberg D, et al: Functional and nutritional assessment of chroni-cally critically ill patients undergoing weaning: a prospective cohort study. Clin Nutr Suppl 2011; 1:27.

20 Villet S, Chiolero RL, Bollmann MD, Revelly JP, Cayeux R N MC, Delarue J, Berger MM: Negative impact of hypocaloric feeding and energy balance on clinical outcome in ICU patients. Clin Nutr 2005; 24:502 509.

21 Dvir D, Cohen J, Singer P: Computerized energy balance and complications in critically ill patients: an observational study. Clin Nutr 2006;25:37 44.

22 Faisy C, Lerolle N, Dacharaoui F, Savard JF, Abdoud I, Tadie JM, Fagon JY: Impact of energy deficit by a predictive method on outcome in medical patients requiring prolonged acute mechanical ventilation. Am J Clin Nutr 2009;101:1079 1087.

23 Singh N, Gupta D, Aggarwal AN, Agarwal R, Jindal SK: An assessment of nutritional support to criti-cally ill patients and its correlation with outcomes in a respiratory intensive care unit. Resp Care 2009;54: 1688 1696.

24 Magnuson B, Peppard A, Auer Flomenhoft D: Hypocaloric considerations in patients with poten-tially hypometabolic disease states. Nutr Clin Pract 2011;26:253 260.

25 Alves VG, da Rocha EE, Gonzalez MC, da Fonseca RB, Silva MH, Chiesa CA: Assessment of resting energy expenditure of obese patients: comparison of indirect calorimetry with formulae. Clin Nutr 2009;28:299 304.

26 Dudrick SJ, Wilmore DW, Rhoads JE: Long- term total parenteral nutrition with growth, development and positive nitrogen balance. Surgery 1968;64:134 142.

27 Bistrian BR, Balckburn GL, Hallowell E, Heddie R: Protein status of general surgical patients. JAMA 1974;230:858 860.

28 McCowen KC, Friel C, Sternberg J, et al: Hypocaloric total parenteral nutrition: effectiveness in preven-tion of hyperglycemia and infectious complications a randomized clinical trial. Crit Care Med 2000; 28:3606 3611.

29 Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in critically ill patients. N Eng J Med 2001;345:1359 1367.

30 Casaer MP, Mesotten D, Hermans G, et al: Early versus late parenteral nutrition in critically ill adults. N Eng J Med 2011;365:506 517.

31 Dissanaike S, Shelton M, Warner K, OKeefe GE: The risk for bloodstream infections is associated with increased parenteral caloric intake in patients receiving parenteral nutrition. Crit Care 2007;11: R114.

32 Grau T, Bonet A, Rubio M, et al: Liver dysfunction associated with artificial nutrition in critically ill patients. Crit Care 2007;11:R10.

33 Grau T, Bonet A: caloric intake and liver dysfunc-tion in critically ill patients. Curr Opin Clin Nutr Metab Care 2009;12:175 179.

34 Weijs PJM, Stapel SN, de Groot SD, et al: Optimal protein and energy nutrition decreases mortality in mechanically ventilated, critically ill patients: a pro-spective observational cohort study. JPEN J Parenter Enteral Nutr 2012;36:60 68.

35 Singer P, Anber R, Cohen J, et al: The Tight Calorie Control Study (TICACOS): a prospective, random-ized, controlled pilot study of nutritional support in critically ill patients. Int Care Med 2011;37:601 609.


36 Heidegger CP, Graf S, Thiebault R, et al: Supplemental parenteral nutrition (SPN) in inten-sive care unit (ICU) patients for optimal energy coverage: improved clinical outcome. Clin Nutr Suppl 2011;1:2 3.

37 Arabi YM, Tamim HM, Dhar GS, et al: Permissive underfeeding and intensive insulin therapy in criti-cally ill patients: a randomized controlled trial. Am J Clin Nutr 2011;93;569 577.

38 Rice TW, Mogan S, Hays MA, Bernard GR, Jensen GL, Wheeler AP: Randomized trial of initial trophic versus full- energy enteral nutrition in mechanically ventilated patients with acute respiratory failure. Crit Care Med 2011;39:967 973.

39 Carlson GL, Dark P: Acute intestinal failure. Curr Opin Crit Care 2010;16:347 352.

40 Wierdsma NJ, Peters JHC, Weijs PJM, et al: Malabsorption and nutritional balance in the ICU feacal weight as a biomarker: a prospective obser-vational pilot study. Crit Care 2011;15:R264.

41 Strack van Schijndel RJM, Wierdsma NJ, van Heijningen EMB, Weijs PJM, de Groot SDW, Girbes ARJ: Fecal energy losses in enterallly fed intensive care patients: an explorative study using bomb calo-rimetry. Clin Nutr 2006;25:758 764.

42 Weekes CE: Controversies in the determination of energy requirements. Proceed Nutr Soc 2007;66: 367 377.

Pierre Singer, MDCritical Care Medicine, Institute for Nutrition ResearchRabin Medical Center, Beilison HospitalIL 49100 Petah Tikva (Israel)Tel. +972 3 9376521, E-Mail [email protected]



Protein Metabolism and RequirementsGianni BioloDepartment 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 muscleF Glutamine effluxF Proteolysis insulin resistance

LiverF GluconeogenesisF Acute phase proteinF Urea synthesisF Albumin synthesis

Increased urinarynitrogen excretion

Amino acids

f Glutamine

F Glucose

F Urea

f Albumin Increased albumintranscapillary escape

Immune systemF Cell turnoverF 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 1.31.5 g/kg ideal body weight/day of a balanced amino acid mixture in con-junction with an adequate energy supply [7]. When parenteral nutrition is indicated in critically ill patients, the amino acid solution should contain 0.20.4 g/kg/day of l- glutamine (e.g. 0.30.6 g/kg/day alanyl- glutamine dipeptide). These recommenda-tions may not apply to all patients. In acutely ill patients receiving hypocaloric feeding, nitrogen requirements may be increased by about 2530% [7].

Acute renal failure is a highly catabolic state due to uremic toxicity, enhanced inflammatory response, metabolic acidosis, insulin resistance, catabolic hormone secretion, and activation of protein catabolism by artificial dialysis membranes. In patients with acute renal failure, starvation further augments the catabolic response and malnutrition has been identified as a major determinant of morbidity and mor-tality. Evidence suggests a higher protein/amino acid requirement in critical illness with acute renal failure [27, 28]; however, the optimal amount of protein/amino acid intake for this condition is unknown.

The ESPEN guidelines suggest that critically ill patients on continuous renal replace-ment therapy should receive about 1.5 g/kg/day of protein/amino acid. As the process of dialysis can remove 1015% of plasma amino acid turnover, a further increase in protein/amino acid intake of 0.2 g/kg/day is required to account for such amino acid losses [29]. In critically ill patients with acute renal failure on conservative therapy, a high protein/amino acid intake accelerates urea production and can increase nitrogen load to the kidney. On the other hand, a low protein/amino acid intake can increase lean body mass wasting and affect patient outcome, while an increased intake may increase renal perfusion and glomerular filtration rate. The optimal amount of pro-tein/amino acid intake in these patients has not been clearly defined. Current guide-lines suggest a protein/amino acid intake up to 1 g/kg/day [29]. Nonetheless, evidence suggests that an increased protein/amino acid intake in nonoliguric acute renal failure patients may improve nitrogen balance without aggravating renal function [30].

The ESPEN guidelines for parenteral nutrition in the intensive care unit recom-mend normalizing protein/amino acid requirements per kg ideal body weight in order to avoid overfeeding in obese or edematous patients. In many studies, protein intake has been normalized per kg actual body weight, while lean body mass is the true deter-minant of protein requirement. Thus, the use of either ideal or actual body weight leads to underfeeding in some patients and overfeeding in others. It has been recently proposed to normalize the protein target per actual body weight only in the case of BMI between 20 and 30. In the case of BMI greater than 30, protein target (g/kg/day) should be multiplied by 27.5 and by the square of height (m). In the case of BMI lower than 20, the protein target (g/kg/day) should be multiplied by 20 and by the square of height (m) [31]. The same authors recommend using preadmission body weight [31].


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.

Proteinamino acid

intakeProtein

degradation

Protein synthesist$POUSBDUJMFQSPUFJOTTLFMFUBMNVTDMFIFBSU

t"DVUFQIBTFQSPUFJOTt*NNVOFTZTUFNQSPUFJOTt"MCVNJOt4USVDUVSBMBOENFNCSBOFDFMMQSPUFJOTt&O[ZNFTt)PSNPOFTtFUDOxidation

Urea

Freeamino acidQPPM

De novo synthesisHMVUBNJOFBMBOJOFFUD

3FHVMBUJPOPGTQFDJDNFUBCPMJDQBUIXBZTt(MVUBNJOFrGVFMGPSJNNVOFDFMMTBOE FOUFSPDZUFTHMVDPOFPHFOFTJTOVDMFJD BDJETZOUIFTJTJOTVMJOTFOTJUJWJUZt"SHJOJOFr nitric oxide synthesist$ZTUFJOFrHMVUBUIJPOFTZOUIFTJTt"MBOJOFrHMVDPOFPHFOFTJTt-FVDJOFrNVTDMFQSPUFJOTZOUIFTJT JOTVMJOTFOTJUJWJUZt5ISFPOJOFrXPVOEIFBMJOHtFUD

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.


1 Plank LD, Connolly AB, Hill GL: Sequential changes in the metabolic response in severely septic patients during the first 23 days after the onset of peritonitis. Ann Surg 1998;228:146 158.

2 Barle H, Hammarqvist F, Westman B, Klaude M, Rooyackers O, Garlick PJ, Wernerman J: Synthesis rates of total liver protein and albumin are both increased in patients with an acute inflammatory response. Clin Sci (Lond) 2006;110:93 99.

3 Biolo G, Zorat F, Antonione R, Ciocchi B: Muscle glutamine depletion in the intensive care unit. Int J Biochem Cell Biol 2005;37:2169 2179.

4 Biolo G, Fleming RY, Maggi SP, Nguyen TT, Herndon DN, Wolfe RR: Inhibition of muscle glu-tamine formation in hypercatabolic patients. Clin Sci (Lond) 2000;99:189 194.

5 Rodas PC, Rooyackers O, Hebert C, Norberg , Wernerman J: Glutamine and glutathione at ICU admission in relation to outcome. Clin Sci (Lond) 2012;122:591 597.

6 Kreymann KG, Berger MM, Deutz NE, Hiesmayr M, Jolliet P, Kazandjiev G, Nitenberg G, van den Berghe G, Wernerman J, DGEM (German Society for Nutritional Medicine), Ebner C, Hartl W, Heymann C, Spies C, ESPEN (European Society for Parenteral and Enteral Nutrition): ESPEN Guidelines on Enteral Nutrition: intensive care. Clin Nutr 2006;25:210 223.

7 Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, Griffiths R, Kreyman G, Leverve X, Pichard C, ESPEN: ESPEN Guidelines on Parenteral Nutrition: intensive care. Clin Nutr 2009; 28:387 400.

8 Friedrich O: Critical illness myopathy: what is hap-pening? Curr Opin Clin Nutr Metab Care 2006;9: 403 409.

9 Biolo G, Fleming RY, Maggi SP, Nguyen TT, Herndon DN, Wolfe RR: Inverse regulation of pro-tein turnover and amino acid transport in skeletal muscle of hypercatabolic patients. J Clin Endocrinol Metab 2002;87:3378 3384.

10 Hassan- Smith Z, Cooper MS: Overview of the endocrine response to critical illness: how to mea-sure it and when to treat. Best Pract Res Clin Endocrinol Metab 2011;25:705 717.

11 Biolo G, De Cicco M, Lorenzon S, Dal Mas V, Fantin D, Paroni R, Barazzoni R, Zanetti M, Iapichino G, Guarnieri G: Treating hyperglycemia improves skele-tal muscle protein metabolism in cancer patients after major surgery. Crit Care Med 2008;36:1768 1775.

12 Powers SK, Smuder AJ, Criswell DS: Mechanistic links between oxidative stress and disuse muscle atrophy. Antioxid Redox Signal 2011;15:2519 2528.

13 Biolo G, Ciocchi B, Lebenstedt M, Barazzoni R, Zanetti M, Platen P, Heer M, Guarnieri G: Short- term bed rest impairs amino acid- induced protein anabolism in humans. J Physiol 2004;558:381 338.

14 Biolo G, Ciocchi B, Stulle M, Bosutti A, Barazzoni R, Zanetti M, Antonione R, Lebenstedt M, Platen P, Heer M, Guarnieri G: Calorie restriction accelerates the catabolism of lean body mass during 2 wk of bed rest. Am J Clin Nutr 2007;86:366 372.

15 Ferrando AA, Stuart CA, Sheffield- Moore M, Wolfe RR: Inactivity amplifies the catabolic response of skeletal muscle to cortisol. J Clin Endocrinol Metab 1999;84:3515 3521.

16 Biolo G, Tipton KD, Klein S, Wolfe RR: An abun-dant supply of amino acids enhances the metabolic effect of exercise on muscle protein. Am J Physiol 1997;273:E122 E129.

17 Winkelman C, Johnson KD, Hejal R, Gordon NH, Rowbottom J, Daly J, Peereboom K, Levine AD: Examining the positive effects of exercise in intu-bated adults in ICU: a prospective repeated mea-sures clinical study. Intensive Crit Care Nurs 2012, E- pub ahead of print.

18 Rennie MJ: Anabolic resistance in critically ill patients. Crit Care Med 2009;37(10 Suppl): S398 S399.

19 Elwyn DH: Nutritional requirements of adult surgi-cal patients. Crit Care Med 1980;8:9 20.

20 Biolo G, Agostini F, Simunic B, Sturma M, Torelli L, Preiser JC, Deby- Dupont G, Magni P, Strollo F, di Prampero P, Guarnieri G, Mekjavic IB, Pisot R, Narici MV: Positive energy balance is associated with accelerated muscle atrophy and increased erythrocyte glutathione turnover during 5 wk of bed rest. Am J Clin Nutr 2008;88:950 958.

21 Wolfe RR, Goodenough RD, Burke JF, Wolfe MH: Response of protein and urea kinetics in burn patients to different levels of protein intake. Ann Surg 1983;197:163 171.

22 Ishibashi N, Plank LD, Sando K, Hill GL: Optimal protein requirements during the first 2 weeks after the onset of critical illness. Crit Care Med 1998;26: 1529 1535.

23 Larsson J, Lennmarken C, Mrtensson J, Sandstedt S, Vinnars E: Nitrogen requirements in severely injured patients. Br J Surg 1990;77:413 416.

24 Pitknen O, Takala J, Pyhnen M, Kari A: Nitrogen and energy balance in septic and injured intensive care patients: response to parenteral nutrition. Clin Nutr 1991;10:258 265.

25 Greenberg GR, Jeejeebhoy KN: Intravenous protein- sparing therapy in patients with gastrointestinal dis-ease. JPEN J Parenter Enteral Nutr 1979;3:427 432.

References

20 Biolo

26 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.

27 Macias WL, Alaka KJ, Murphy MH, Miller ME, Clark WR, Mueller BA: Impact of the nutritional regimen on protein catabolism and nitrogen bal-ance in patients with acute renal failure. JPEN J Parenter Enteral Nutr 1996;20:56 62.

28 Scheinkestel CD, Kar L, Marshall K, Bailey M, Davies A, Nyulasi I, Tuxen DV: Prospective ran-domized trial to assess caloric and protein needs of critically ill, anuric, ventilated patients requiring continuous renal replacement therapy. Nutrition 2003;19:909 916.

29 Cano NJ, Aparicio M, Brunori G, Carrero JJ, Cianciaruso B, Fiaccadori E, Lindholm B, Teplan V, Fouque D, Guarnieri G, ESPEN: ESPEN Guidelines on Parenteral Nutrition: adult renal failure. Clin Nutr 2009;28:401 414.

30 Singer P: High- dose amino acid infusion preserves diuresis and improves nitrogen balance in nonoliguric acute renal failure. Wien Klin Wochenschr 2007;119:218 222.

31 Weijs PJ, Sauerwein HP, Kondrup J: Protein recom-mendations in the ICU: g protein/kg body weight which body weight for underweight and obese patients? Clin Nutr 2012, E- pub ahead of print.

32 Kreymann G, DeLegge MH, Luft G, Hise ME, Zaloga GP: The ratio of energy expenditure to nitrogen loss in diverse patient groups a system-atic review. Clin Nutr 2012;31:168 175.

33 Singer P, Anbar R, Cohen J, Shapiro H, Shalita- Chesner M, Lev S, Grozovski E, Theilla M, Frishman S, Madar Z: The Tight Calorie Control Study (TICACOS): a prospective, randomized, controlled pilot study of nutritional support in critically ill patients. Intensive Care Med 2011;37:601 609.

34 Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G: Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365:506 517.

35 Strack van Schijndel RJ, Weijs PJ, Koopmans RH, Sauerwein HP, Beishuizen A, Girbes AR: Optimal nutrition during the period of mechanical ventila-tion decreases mortality in critically ill, long- term acute female patients: a prospective observational cohort study. Crit Care 2009;13:R132.

36 Alberda C, Gramlich L, Jones N, Jeejeebhoy K, Day AG, Dhaliwal R, Heyland DK: The relationship between nutritional intake and clinical outcomes in critically ill patients: results of an international mul-ticenter observational study. Intensive Care Med 2009;35:1728 1737.

37 Allingstrup MJ, Esmailzadeh N, Wilkens Knudsen A, Espersen K, Hartvig Jensen T, Wiis J, Perner A, Kondrup J: Provision of protein and energy in rela-tion to measured requirements in intensive care patients. Clin Nutr 2011, E- pub ahead of print.

Gianni Biolo, MD, PhDClinica Medica, Ospedale di CattinaraStrada di Fiume 447IT 34149 Trieste (Italy)Tel. +39 040 399 4532, E- Mail [email protected]



How to Choose the RouteIrina GrecuAnaesthetics 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 dont use the gut, youll lose it. This has been nicely shown in both animal models and humans. After 3 days of luminal nutrient deprivation, a significant loss of intestinal mass, reduction of villous height and crypt depth, and increased intestinal permeability could be demonstrated [12, 13]. Moreover, a recent trial including 28 critically ill patients randomized to receive either early (within 24 h from admission) or delayed (after 4 days) gastric

24 Grecu

feeding showed significant impairment of the intestinal absorptive capacity (as inves-tigated for glucose absorption) in the delayed enteral nutrition group, despite similar gastric emptying times [14]. In the delayed feeding group, an increase in the duration of mechanical ventilation and in the length of ICU stay was shown, although mortal-ity was similar in both groups (but the trial was not powered for this endpoint) [14].

This finding is consistent with previous trials and a meta- analysis showing that early enteral nutrition (compared to standard practice) decreases morbidity and mor-tality in critically ill patients [15].

From a practical perspective, feeding the gut, also named trophic or trickle feed-ing, or minimal enteral nutrition in earlier textbooks, means continuous delivery of small amounts of nutrition formula into the stomach or jejunum at a rate of 10 30 ml/h starting within the first 24 to maximum 48 h from admission in the ICU, with the goal of maintaining gut integrity and function while decreasing complications [16].

Considering the second goal of enteral nutrition, feeding the gut does not mean we are feeding the patient as a whole, fulfilling his increased metabolic requirements in order to support disease resolution, wound healing, and recovery. Self- evidently, higher administration rates than the ones used for trickle feeding are required to deliver the whole energy intake, measured or estimated. Unfortunately, gastrointes-tinal intolerance is common in critically ill patients, directly correlates with disease severity, and precludes full or near target enteral nutrition delivery, leading to under-feeding. When prolonged beyond the first week after admission, underfeeding has been shown to increase energy (and protein) debt and thus increase complications and length of stay in critically ill patients [17, 18].

On the other hand, there might be some categories of ICU patients who can toler-ate a limited period of underfeeding, at least in the first 5 6 days after admission, pro-vided they are still receiving early enteral trickle feeding, as it has recently been shown in an RCT that included overweight, predominantly female, mechanically ventilated, single- organ (acute respiratory) failure patients [19]. Understandably, all the trials investigating delayed feeding [14, 19] have not included previously malnourished or very severely ill patients. The rationale behind this is these categories of patients are either highly catabolic or have a priori reduced reserves and will therefore have worse outcomes if not receiving both early and adequate nutritional support. Unfortunately, this rationale is not supported by much clinical evidence thus far [4, 20, 21], and it will be very difficult to conduct such trials from an ethical perspective.

Another common problem with enteral nutrition is the difference between pre-scription and actual delivery. Even if an early start has been achieved through the enteral route, when auditing the actual practice results are unanimously disappoint-ing: only 59% of target energy and 56% of target protein intake are actually delivered within the first 12 days of stay in the ICU, as shown in a large multicenter trial includ-ing 2,772 patients in 167 ICUs from 21 countries [22]. Interestingly, the study also showed that increasing energy intake by 1,000 kcal/day and protein intake by 30 g/day resulted in a significant decrease in mortality rate and increase in ventilator- free days


in patients with BMI

26 Grecu

supplementing the enteral with parenteral route in order to achieve early target energy and protein intake. Indeed, in practice, many ICUs throughout Europe are using this approach more and more frequently.

Paradoxically, there is a paucity of trials in the literature looking at combined enteral and parenteral nutrition. A meta- analysis published in 2004 [29] found no clinical benefit and recommended against routine parenteral supplementation to enteral nutrition when the latter is insufficient. This meta- analysis included five tri-als, one of which was an extension of an older trial, and of the remaining four RCTs, three had important flaws [20].

While ESPEN recommends the introduction of supplemental parenteral nutrition (SPN) after the first 2 days from enteral feed initiation, if this is insufficient (


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 (

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

kcal

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

kcal

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 daysOral diet possible or expected toresume within 3 daysPalliative care

Can EN be started within 24 h? Start early TPN Reassess daily if EN possible

Start gastric feed at 20 ml/hIncrease by 20 ml/h every 6 hAccept GRV up to 500 ml

Is EN tolerated 60% of target delivery at 72 h?

Is minimal EN possible?

Continue ENIncrease to 100% target*

Add SPN up to 100%energy and protein target

Reassess daily for SPN needDecrease SPN as EN tolerance increasesMonitor for complications (infectious, metabolic)Consider resuming oral diet

Yes

No

Yes

Yes

Yes

Yes

No

No

No

Start minimal ENAdd SPN up to 100% target

Fig. 2. Proposed algorithm for choosing the route for nutrition delivery in critically ill. EN = Enteral nutrition; PN = parenteral nutrition; GRV = gastric residuals volume; TPN = total parenteral nutrition. * At this point, methods to increase EN delivery could be tried (if not already) to reach 100% energy and protein goals: prokinetics, postpyloric feeding, etc. If jejunal feeding is used, then intra- abdominal pressure should be monitored.

30 Grecu

1 Berger MM, Chiolero RL, Pannatier A, Cayeux MC, Tappy L: A 10- year survey of nutritional support in a surgical ICU: 19861995. Nutrition 1997;13: 870877.

2 Gramlich L, Kichian K, Pinilla J, Rodych NJ, Dhaliwal R, Heyland DK: Does enteral nutrition compared to parenteral nutrition result in better outcomes in critically ill adult patients? A system-atic review of the literature. Nutrition 2004;20: 843 848.

3 Singer P, Pichard C: Parenteral nutrition is not the false route in intensive care unit. JPEN J Parenter Enteral Nutr 2012;36:12 14.

4 Kreymann KG, Berger MM, Deutz NE, et al: ESPEN Guidelines on Enteral Nutrition: intensive care. Clin Nutr 2006;25:210 223.

5 NIHR Health Technology Assessment: Clinical and cost- effectiveness of early parenteral compared with early enteral nutritional support in critically ill patient study (CALORIES). http://www.hta.ac.uk/project/1760.asp.

6 Peter JV, Moran JL, Philips- Hughes J: A metaanaly-sis of treatment outcomes of early enteral versus early parenteral nutrition in hospitalized patients. Crit Care Med 2005;33:213 220.

7 Simpson F, Doig GS: Parenteral vs enteral nutrition in the critically ill patient: a meta- analysis of trials using the intention to treat principle. Intensive Care Med 2005;31:12 23.

8 Griffiths RD: Guidelines for nutrition in the criti-cally ill: are we altogether or in- the- altogether? JPEN J Parenter Enteral Nutr 2010;34:595 597.

9 Woodcock NP, Zeigler D, Palmer MD, Buckley P, Mitchell CJ, MacFie J: Enteral versus parenteral nutrition: a pragmatic study. Nutrition 2001;17: 1 12.

10 DeWitt RC, Kudsk KA: The guts role in metabo-lism, mucosal barrier function and gut immunol-ogy. Infect Dis Clin North Am 1999;13:465 481.

11 Stapleton RD, Jones N, Heyland DK: Feeding critically ill patients: what is the optimal amount of energy? Crit Care Med 2007;35(Suppl 9): S535S540.

12 Levin RJ: Digestion and absorption of carbohy-drates from molecules and membranes to humans. Am J Clin Nutr 1994;59:690S698S.

13 Caspary WF: Physiology and pathophysiology of intestinal absorption. Am J Clin Nutr 1992;55: 299S308S.

start: it preserves the gut function if delivered enterally and decreases mortality as compared to late start, regardless of route (enteral or parenteral).

It is less clear, however, what adequate includes: it certainly means avoiding over-feeding, but also prolonged underfeeding. The controversial results in clinical out-comes of recent trials studying full target delivery versus underfeeding might be explained by the differences in defining the optimal target in the control group and the different populations of patients included (in terms of acute pathology, but also previous nutritional status), and certainly request redefining adequate nutrition more specifically, disease- related (including the stage of disease) and patient- related. Moreover, adequate refers equally to the composition of food, as some substrates proved to positively influence clinical outcomes (i.e. glutamine, selenium, fish oil, etc.).

The decision- making in choosing the route is a stepwise process looking at the possibility and adequacy of first using the oral route, then the enteral (gastric as a first intention) and if not possible, the parenteral route. Early combination of enteral and parenteral nutrition is a rational approach in previously malnourished or in very severely ill patients, with a high probability of prolonged gastrointestinal intolerance. This approach should be further investigated in well- designed and - conducted RCTs in order to translate rationale into practice.

References


14 Nguyen NQ, Besanko L, Burgstad C, et al: Delayed enteral feeding impairs intestinal carbohydrate absorption in critically ill patients. Crit Care Med 2012;40:50 54.

15 Doig GS, Heighes PT, Simpson F, et al: Early enteral nutrition, provided within 24 h of injury or inten-sive care unit admission, significantly reduces mor-tality in critically ill patients: a meta- analysis of randomised controlled trials. Intensive Care Med 2009;35:20182027.

16 McClave SA, Martindale RG, Vanek VW, et al: Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr 2009;33:277316.

17 Villet S, Chiolero RL, Bollmann MD, et al: Negative impact of hypocaloric feeding and energy balance on clinical outcome in ICU patients. Clin Nutr 2005; 24:502 509.

18 Dvir D, Cohen J, Singer P: Computerized energy targeting adapted to the clinical conditions balance and complications in critically ill patients: an obser-vational study. Clin Nutr 2003;25:37 44.

19 Rice TW, Mogan S, Hays MA, Bernard GR, Jensen GL, Wheeler AP: Randomized trial of initial trophic versus full- energy enteral nutrition in mechanically ventilated patients with acute respiratory failure. Crit Care Med 2011;39:967 973.

20 Singer P, Berger MM, Van den Berghe G, et al: 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 Clin Proc 2006;81:809 818.

22 Alberda C, Gramlich L, Jones N, Jeejeebhoy K, Day AG, Dhaliwal R, Heyland DK: The relationship between nutritional intake and clinical outcomes in critically ill patients: results of an international mul-ticenter observational study. Intensive Care Med 2009;35:1728 1737.

23 OMeara D, Mireles- Cabodevila E, Frame F, et al: Evaluation of delivery of enteral nutrition in criti-cally ill patients receiving mechanical ventilation. 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 reduced by a two- step quality improvement of nutrition therapy: the intensive care dietitian can make the difference. Crit Care Med 2012;40: 412 419.

25 Doig GS, Simpson F, Finfer S, et al: Effect of evidence- based feeding guidelines on mortality of critically ill adults: a cluster randomized controlled trial. JAMA 2008;300:2731 2741.

26 Poulard F, Dimet J, Martin- Lefevre L, et al: Impact of not measuring residual gastric volume in mechanically ventilated patients receiving early enteral feeding: a prospective before- after study. JPEN J Parenter Enteral Nutr 2010;34:125130.

27 Casaer MP, Mesotten D, Hermans G, et al: Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365:506 517.

28 Hegazi RA, Wischmeyer PE: Clinical review: opti-mizing enteral nutrition for critically ill patients a simple data- driven formula. Crit Care 2011;15:234.

29 Dhaliwal R, Jurewitsch B, Harrietha D, Heyland 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.

30 Singer P, Anber R, Cohen J, et al: The Tight Calorie Control Study (TICACOS): a prospective, random-ized, controlled pilot study of nutritional support in critically ill patients. Intensive Care Med 2011;37: 601 609.

31 Heidegger CP, Graf S, Thibault R, Darmon P, Berger M, Pichard C: Supplemental parenteral nutrition (SPN) in intensive care unit (ICU) patients for opti-mal energy coverage: improved clinical outcome. Clin Nutr Suppl 2011;1:2 3.

32 Heidegger C- P, Romand J- A, Tregiarri MM, Pichard C: Is it time to promote mixed enteral and paren-teral nutrition for the critically ill patient? Intensive Care Med 2007;33:963 969.

Irina Grecu, MD, PhD Anaesthetics Department, University College Hospital235 Euston Road, London NW1 2BU (UK)E- Mail [email protected]



How to Prescribe Nutritional Support Using ComputersMette M. BergerService 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. Copyright 2013 S. Karger AG, Basel

The critically ill patient is admitted to the intensive care unit (ICU) to benefit from various types of organ support, including nutritional support. Although not lifesav-ing, nutrition has been shown to significantly influence outcome [1 3], contributing to the success or failure of other treatments. When the quality of the support is poor, in either under- or overfeeding or with inappropriate use of feeding techniques, the outcome worsens.

Several process changes have been attempted to improve ICU nutritional therapy: standardization of practice and introduction of evidence- based treatments are in the first line of the improvements. Guidelines have improved clinical practice signifi-cantly, but have failed to achieve optimization of energy delivery. This lack of impact on energy delivery was confirmed in a large cluster randomized trial enrolling 1,118 patients from 27 ICUs conducted in Australia and New Zealand which compared guideline and control ICUs: the 18- point evidence- based guideline promoted ear-lier feeding and greater nutritional adequacy, but did not improve clinical outcomes nor energy delivery in a significant way [4].

How to Prescribe Nutritional Support Using Computers 33

What can computers and computerized information systems (CIS) do for nutri-tional therapy? It has been shown that CIS may be useful in several areas, espe-cially in assisting with ancillary tasks [5] (table 1); however, it is particularly able to ensure the safety of the nutrition process due to the possibility to monitor nutrition therapy. Answering the question of the aim matters as there are important eco-nomic issues behind the choice of a computer system. The installation of the most advanced CIS linking all the beds of an ICU costs about EUR 20,000 30,000 per bed, while a high- quality hand- held individual computer costs only around EUR 1,000.

The use of computerized systems to assist nutritional support is not new, as one of the first papers was published in 1986 [6]. The first described aims were to document individual patient demographic and anthropometric data, nutri-tional disorder(s), laboratory data, nutritional support therapy, patient response criteria, and concomitant drug therapy. Research options were immediately identified with the constitution of data bases. In the beginning, there was a distinction between the capacities of the portable and fixed devices [7]; however, with iPads and other personal digital assistants, this distinction is no longer per-tinent. But one major advantage is to finally increase the visibility of nutritional

Table 1. Computerized nutritional assistance

Function Aim

Electronic health records Patient history

Calculators of the most frequently used formulas Predictive energy requirement equations

Prescription tools with strict constraints, e.g. computerized prescriber order entry for PN

Parenteral nutrition safety

Calculation of delivered quantities of substrates (glucose, lipids, proteins) whatever the source, including from drug dilution solutions

Monitoring

Customized screen providing energy balance calculation, laboratories (urea, glucose, prealbumin, triglycerides, ASAT, ALAT), intestinal function (stools, gastric residuals), drugs (insulin)

Supervision at distance Integrative monitoring of actual nutrition delivery by the nurses/dieticians in all the beds of an ICU

Alert systems Detecting early glucose changes (hypo- or hyperglycemia)

Clinical decision- making Integrative

Generation of reports Transmission to ward teams about nutrition in the ICU

Access to Web- based knowledge and guidelines Self- teaching evidence- based medicine

34 Berger

therapy [8]. The text below will discuss the potential of the various forms of computers.

Nutrition Prescription Process

Before any prescription can be made, it is essential to determine the patients met-abolic requirements. Setting up a feeding plan with determination of the energy and protein requirements is indeed the first step. In the vast majority of cases, the energy targets will remain an estimation, but require knowing at least the patients weight, height, BMI, sex, and age. While the latter two are always available, weight and height are sometimes really hard to get only being estimated in about 30 40% of our patients [9]. The computerized system can integrate multiple equations (table 2), including one enabling the determination of height from the knee height mea-surement (Chumlea equation) [10], and hence the determination of the ideal body

Table 2. Examples of equations that can be integrated into computers, to assist estimation of energy requirements

Name Formula

Chumlea equation [10] Stature- men = (2.02 KH cm) (0.04 age) + 64/19Stature- women = (1.83 KH cm) (0.24 age) + 84/8

Harris- Benedict Men: 66 +13.8 (weight in kg) + 5 (height in cm) 6.8 (years)Women: 655 +9.6 (weight in kg) +1.8 (height in cm) 4.7 (years)To be used crude without a stress adjustment

Fleisch (age 2099 years) [31] Men: REE = 24 BSA (38 0.073 (age 20))Women: REE = 24 BSA (35.5 0.064 (age 20))BSA = weight (kg)0.425 height (cm)0.725 71.84

Faisy- Fagon for patients on mechanical ventilation [32]

REE (kcal/day) = 8 body weight + 14 height + 32 VE + 94 body temperature 4834

Penn State 2010 [33] For patients with BMI

How to Prescribe Nutritional Support Using Computers 35

weight from tables. Other energy- predictive equations based on age, sex, weight, and height such as the Harris- Benedict or any other preferred equation may then be integrated. The standard weight- based equations can of course also be included, although all these equations have shortcomings, and we now know that the target of 25 30 kcal/kg/day is too elevated in the majority of patients during the early phase of acute disease.

The industry and several patient associations have developed applications for per-sonal digital assistants that are easy to upload [7]: useful for the individual patient, these applications are by definition limited to the single patient, but the use of calcu-lators is certainly better than nothing.

Computerized Parenteral Nutrition Ordering

While enteral nutrition generally is based on industrial solutions, this is not always the case for parenteral nutrition (PN), for which both industrial bags and individual compounding are used [11]. Due to the multiple possible errors involved with the lat-ter, computerized prescription order entry is advocated for PN, and is recommended by the nutrition societies ASPEN [12] and ESPEN. These systems improve safety [13], particularly in the pediatric context which is the most heavily dependent on individu-alized prescription.

Using the widely available M

117610880 Nutrition in Intensive Care Medicine Beyond Physiology

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