Do Immunonutrients Improve Outcome in the Critically Ill?

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Do Immunonutrients Improve Outcome in the Critically Ill? Caitlin S. Curtis, Kenneth A. Kudsk

Treatment for critically ill patients changes continuously. This is driven, at least in part, by a better understanding of disease processes, advances in technology, and new pharmaceutical and nutraceutical agents. Nutritional support of the critically ill patient had advanced radically during the past 30 years. This reflects the advent of parenteral nutrition and the development of specialized enteral nutrition formulas.1 Enteral nutrition remains the preferred form of nutrition support in the critically ill patient when the gastrointestinal tract is functional.2–7 Several manufacturers include immunemodifying agents in enteral nutrition formulas in attempts to modulate the immune system and improve clinical outcome.

PATHOPHYSIOLOGY AND MECHANISM OF ACTION Defining the mechanism of action for immunonutrition is difficult because this term loosely describes enteral formulas with one or more of the following additives: arginine, glutamine, nucleotides (RNA), omega-3 fatty acids, and branched-chain amino acids (BCAAs). The literature generally classifies formulas containing any or all of these components as immune-enhancing diets (IEDs).1,8–11

function of T lymphocytes, B lymphocytes, lymphokineactivated killer cells, and macrophages.17–20 Finally, glutamine serves as a primary energy substrate for enterocytes and plays an important role in proliferation of the intestinal mucosa and other cell types.20–23

Nucleotides (RNA) Nucleotides (purines and pyrimidines) stimulate the immune system in several ways.24 Nucleotides influence the production of a multitude of cell types in the central and peripheral immune system, including peripheral T cells, pluripotent hemopoietic stem cells, and cells in the thymus. They have key roles in cell-mediated immunity by stimulating T cells to produce growth factors such as interleukin-2 (IL-2), IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF),21,22 which are critical in immune response. Nucleotides are also needed for bacterial and fungal killing; therefore, they are essential for the immune system to overcome infection.25–28

Omega-3 Fatty Acids

Arginine affects the immune system in two ways. First, it is metabolized by inducible nitric oxide synthetase (iNOS). Second, this amino acid is a substrate for arginase 1.11,12 iNOS converts arginine into nitric oxide, a potent oxidant that aids immune cells in both intracellular and extracellular bacterial killing. Arginase 1 metabolizes arginine into ornithine, a precursor for polyamines and proline, which stimulate cell repair and encourage wound healing.13–15

Omega-3 fatty acids, usually supplemented in the form of eicosapentaenoic acid and docosahexaenoic acid, influence the production of inflammatory mediators.29 Specifically, omega-3 fatty acids downregulate inflammatory eicosanoid production from arachidonic acid. This results in the production of the 2 and 4 series of prostaglandins, which are less inflammatory than the proinflammatory 3 and 5 series stimulated by omega-6 fatty acids. These alterations decrease the production of inflammatory cytokines such as IL-1 and tumor necrosis factor (TNF).30 Omega-3 fatty acids dampen the inflammatory response in states in which excessive inflammation is detrimental. Omega-3 fatty acids are usually derived from fish oil, borage oil, or canola oil.31

Glutamine

Branched-Chain Amino Acids

The nonessential amino acid glutamine becomes conditionally essential in the face of stress such as inflammation or injury.16 Glutamine also upregulates the immune system by providing fuel to immune cells and encouraging clonal proliferation. Glutamine directly enhances the

BCAAs are essential amino acids metabolized almost exclusively by the muscle and provide an important precursor of glutamine.32 BCAA administration may exert positive effects on amino acid and protein profiles in septic patients.33

Arginine

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DO IMMUNE-ENHANCING DIETS IMPROVE OUTCOMES IN CRITICALLY ILL PATIENTS? The lack of uniformity of trial design and the outcomes in patients administered IEDs makes this question difficult to answer, even with several meta-analyses available.8–11 The meta-analyses and the trials they analyze lack homogeneity. In analyzing these trials, the reader should pay attention to four key areas: (1) the trials’ definition of immunonutrition, (2) timing of initiation of feeds, (3) amount of formula infused and whether the patients reached their goals in terms of kilocalories and protein, and (4) the patient population studied. All these factors may influence outcomes.

Interpretation, integration, and application of the results from these multiple trials and meta-analyses to an individual patient thus prove difficult. The trials and the meta-analyses have varying types and doses of nutrients as well as different populations of patients and different outcomes. Pharmacologically, decisions regarding the effectiveness of a particular medication require data with standardization of doses, routes, and (most important) the same medication for every patient! For example, medical investigators would never test all known antibiotics against a particular species of bacteria and, then, when only a few antibiotics are determined to be effective against that bacteria, conclude that “all antibiotics are ineffective against the bacteria in question.” So, it is important to evaluate what, when, and in what population immunonutrition was effective.

Immunonutrition Some trials use commercially available products, such as Impact, Immun-Aid, Oxepa, and Stresson. Other trials have various combinations and doses of arginine, glutamine, BCAAs, omega-3 fatty acids, and RNA, given as supplementation to standard isonitrogenous enteral feeding products. The definition of immunonutrition often varies from trial to trial, a fact that should warn the reader regarding the generalizability and validity (or lack thereof) of the results.

Timing of Initiation of Feeding The timing of instituting feeding also varied among the trials. Because several trials in critically ill patients suggest that early enteral feeding is associated with lower infectious complications, time to initiation of feeds is an important variable. Also, because timing is important for many interventions in the treatment of critically ill patients (e.g., antibiotics,34 activated protein C therapy,35 and goaldirected volume repletion),36 timing may also be critical for the success (or failure) of immunonutrition.

Doses and Kilocalories The amount of enteral formula infused, calculation of goal kilocalories, and whether patients reach their caloric goals are important variables in trials. Again, if we consider the different immunonutrients as drugs, the doses of these nutrients (reported in terms of how much enteral formula is infused) may be important. Calculation of goal calories and whether the patients reached their goals are important for the same reasons.

Population The populations studied also may have a bearing on the success or lack of success of IEDs. Although some trials focus on a generic “critically ill” population, others hone in on a specific subset of critically ill patients (septic, trauma, burn, acute respiratory distress syndrome [ARDS], or surgical patients). It is important to recognize the different groups studied and the effectiveness or lack of effectiveness that IEDs have in each subgroup.

BENEFICIAL EFFECTS OF IMMUNEENHANCING DIETS IN SPECIFIC POPULATIONS OF CRITICALLY ILL PATIENTS Critically Ill Trauma Patients The critically ill trauma population is one of the most studied populations showing beneficial effects of IEDs. A summary of trials is available in Table 67-1.37–41 Four of the five trials showed statistically significant positive patient outcomes, namely, fewer infectious complications and shorter length of hospital stay, when IEDs were used. When these and other trials were grouped into metaanalyses, both Beale8 and Montejo11 agreed that IEDs shorten time on mechanical ventilation in trauma patients. Montejo11 and Beale8 and their colleagues concluded that IEDs are beneficial in trauma patients, with evidence of lowered incidence of bacteremia and intra-abdominal infections, although there was insufficient evidence that IEDs lower the incidence of nosocomial pneumonia, wound infection, urinary tract infection, sepsis, ARDS, or multiple-organ dysfunction syndrome (MODS). Montejo and associates11 concluded that IEDs decrease ICU length of stay in trauma patients.

Critically Ill Surgical Patients See Table 67-2 for a summary of trials in critically ill surgery patients.42–44 These trials report positive outcomes when IEDs are used, even though mortality was not significantly affected in any trial. When these and other trials were grouped into meta-analyses, Beale8 and Montejo11 and their colleagues agreed that IEDs decrease infection rate and decrease hospital length of stay of surgical patients.

Critically Ill Burn Patients In comparison with other populations, the use of IEDs in the critically ill burn population is not well studied. One study focusing on burn patients45 compares a low-fat enteral formula supplemented with fish oil to a standard diet (35% fat) and concludes that fish oil did not improve

Chapter 67 Do Immunonutrients Improve Outcome in the Critically Ill?

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Table 67-1 IEDs in Critically Ill Trauma Patients Study

ImmuneEnhancing Diet

Timing

Kilocalorie Goals

Amount Delivered

Statistically Significant Outcomes

Brown et al, 199437

Diet with arginine, a-linoleic acid, and b-carotenes

Within 7 days of injury

35 kcal/kg/day and 1.5 g protein/day

All patients received more than 85% of the caloric goal at day 3

IEDs: fewer infections, better nitrogen balance, and lower CRP

Kudsk et al, 199638

Immun-Aid

24 hr after surgery

0.32–0.38 g nitrogen/kg/day

Mean nitrogen intake for both groups was 0.23 g/kg/day

IEDs: fewer infections, shorter hospital length of stay

Mendez et al, 199739

Diet supplemented with arginine, trace elements and canola oil

First 3 days of admission

30 kcal/kg/day and 1.5 g protein/kg/day

All patients reached 85% of the caloric goal by day 3

No significant differences in outcomes

Moore et al, 199440

Immun-Aid

24 hr after trauma

35 kcal/kg/day in the first 72 hours

NS between groups

IEDs: fewer abdominal abscesses, fewer new multiorgan failure cases

Weimann et al, 199841

Impact

48 hr after trauma

35-40 kcal/kg/day

Not reported

IEDs: fewer days of SIRS or multiorgan failure

CRP, C-reactive protein; IED, immune-enhancing diet; NS, not significant.

Table 67-2 IEDs in Critically Ill Surgical Patients Study

ImmuneEnhancing Diet

Timing

Goals

Delivered

Statistically Significant Outcomes

Daly et al, 199242

Impact

Within 12 hr after surgery

25 kcal/kg/day

NS between groups

IEDs: fewer infections and wound complications and shorter LOS

Gianotti et al, 199743

Impact

6 hr after surgery

105 kJ/kg/day

Only 6.3% in each group failed to reach the nutrition goal

IEDs: shorter LOS and better immune profile

Senkal et al, 199744

Impact

12 hr after surgery

25 kcal/kg/day Inclusion criteria of tolerance of 3000 mL of formula

All patients received at least 3000 mL of formula

IEDs: lower cost and lower number of late complications

IED, immune-enhancing diet; LOS, length of stay; NS, not significant.

clinical outcomes. Peng and coworkers46 supplemented glutamine in addition to standard enteral formulas and showed that the IED improved wound healing and reduced length of hospital stay. Another trial by Garrel and associates47 showed decreased infectious complications when burn patients were given formulas supplemented with glutamine. Therefore, glutamine supplementation may provide some clinical benefit in burn patients, but there is no evidence to support other immune-enhancing ingredients in this population.

Overall Critically Ill Patients Within the overall critically ill population, trials vary in their inclusion criteria and target population. Although some investigators study IEDs in all critically ill patients, others narrow their inclusion criteria to include only subsets. For example, some trials focus on septic patients,

some focus on ARDS patients, and some focus on mechanically ventilated patients with severe sepsis and septic shock. A summary of these trials is found in Table 67-3.48–55 Looking at these trials, it is important to note that the benefits of IEDs are seen in a targeted population when enteral nutrition is initiated early (within 24 hours) in the hospital stay. Overall, IEDs improve oxygenation in mechanically ventilated patients with sepsis or ARDS. In some trials, IEDs offer a mortality benefit, whereas in others, they do not. As for the meta-analyses, they offer conflicting opinions. Beale and associates8 conclude that IEDs decrease infection rate overall, while Heyland and colleagues9 maintain that IEDs have no effect on rate of infectious complications. All metaanalyses8–11 agree that the use of IEDs decreases hospital length of stay, although Montejo and associates11 argue that this only occurs in surgical patients. All these authors8–11 conclude that IEDs fail to affect mortality.

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Table 67-3 IEDs in Various Populations of Critically Ill Medical Patients Study

ImmuneEnhancing Device

Timing

Goals

Delivered

Outcomes

Atkinson et al, 199848

Impact

Within 72 hr of admission

>2.5 L of formula

Nonsignificant between groups

IEDs: lower duration of mechanical ventilation and shorter hospital stay

Bower et al, 199549

Impact

Within 48 hr of event causing ICU admission

Up to 1.25 times REE

Both groups received 75% to 85% of what was ordered

Of patients who received 821 mL/day, IEDs showed shorter LOS and fewer infections.

Gadek et al, 199950 (ARDS patients)

Oxepa

Within 24 hr of randomization

75% of BEE  1.3, Harris-Benedict

All included patients received goal calories for a minimum of 4  1 days from study day 1

IEDs: fewer days of MV and shorter LOS in ICU; lower incidence of new organ failure

Galban et al, 200051 (septic patients)

Impact

Within 36 hr of sepsis

1.3  HarrisBenedict

Nonsignificant between groups

IEDs: lower mortality rate and lower number of bacteremias and nosocomial infections

Kieft et al, 200552

Stresson Multi Fibre

Within 48 hr of admission to the ICU

Harris-Benedict  stress factor of clinician’s choice

Patients received 62.8% to 72.5% of required

IEDs: no significant benefits

Pacht et al, 200353 (ARDS)

Oxepa

Within 24 hr of meeting study criteria

50% of HarrisBenedict  1.33

Nonsignificant between groups

IEDS: improved oxygenation and decrease in inflammatory cytokines and cells in BAL fluid

Pontes-Arrudas et al, 200654 (severe sepsis and septic shock)

Oxepa

Within 6 hr of meeting study criteria

75% of BEE V 1.3, Harris-Benedict within 72 hr

Nonsignificant between groups

IEDs: mortality benefit and better oxygenation; fewer days of MV, fewer ICU days, and fewer new organ dysfunction

Singer et al, 200655 (ARDS)

Pulmocare

Within 24 hr of ICU admission

70% of REE  1.2

All patients received enteral nutrition for 14 days at a rate not exceeding REE  1.25

IEDs: improvement in oxygenation, lung compliance; fewer days of MV; no mortality benefit

ARDS, acute respiratory distress syndrome; BAL, bronchoalveolar lavage; BEE, basal energy expenditure; ICU, intensive care unit; IED, immune-enhancing diet; LOS, length of stay; MV, mechanical ventilation; REE, resting energy expenditure.

IMMUNE-ENHANCING DIETS AND MORTALITY Controversy surrounds issues of mortality differences with IEDs. Most trials fail to show a mortality benefit with IEDs. The trials that show a mortality benefit51,54 have in common that enteral nutrition is initiated early in the ICU course and advanced to goal rate within a predefined time frame, usually 48 hours. All meta-analyses8–11 agree that IEDs produce no effects on overall patient mortality, but individual trials show conflicting results, especially in septic patients. The study by Galban and colleagues51 documented a significant reduction in mortality with IEDs, whereas in Bower and associates’ study,49 results approached significance for a higher relative risk for death with immunonutrition. This particular trial noted that the increased mortality occurred in patients classified as “unsuccessful feeders.” Montejo and associates,11 in

their meta-analysis, performed a subgroup analysis of burn, surgical, and trauma patients and found that IEDs failed to affect mortality. All meta-analyses8–11 concluded that IEDs generate no overall effect on mortality in critically ill patients.

Interpretation Although interpretation of these trials is challenging, they provide uniformity and consistency in some conclusions. Overall, IEDs decrease infectious complications and hospital length of stay, with little or no effect on overall mortality. Results of clinical trials provide better evidence of benefit and effectiveness of IEDs in trauma and surgical patients with less evidence in mixed populations of critically ill patients. The influence of variables such as specifically responsive populations, optimal time for initiation of diet, choice and dose of immunonutrients in the diets,

Chapter 67 Do Immunonutrients Improve Outcome in the Critically Ill? and harm versus benefit of arginine in septic patients remains poorly defined from the existing data. With regard to the septic population, Bertolini and coworkers56 state that arginine and omega-3 fatty acids can be associated with opposite effects on the immune system and that “no attempt has been made to target immunonutrients to the different phases . . . and to the haemodynamic conditions of patients.” They concluded that future studies involving immunonutrients should be based on “robust knowledge of basic mechanisms of action” because their caloric and pharmacologic actions have the “potential to greatly influence physiological functions when administered at pharmacological doses.”

CONCLUSION The term immunonutrients remains, at best, ill-defined. It includes nutrients such as glutamine, arginine, omega-3 fatty acids, and nucleotides (among others), either alone or in combination. Existing trials that study nutrient effects in the critically ill population lack uniformity in the number, amount, and combination of these nutrients. A critically ill patient population is by no means a homogeneous population and may include medical, surgical, trauma, and burn patients, as well as septic and nonseptic patients. Although several trials and meta-analyses attempt to determine whether IEDs affect outcome in critical illness, results agree in some areas but disagree in others. It is uniformly agreed that IEDs provide benefit overall in decreasing infectious complications and decreasing length of stay, especially in trauma and surgical populations, but it remains unclear whether immunonutrition harms certain patients (e.g., septic patients). Although there is controversy regarding mortality with IEDs in this subpopulation, the results of the metaanalyses suggest no overall effect. Future trials should include the following: l Standardized number and choice of nutrients l Standardized doses l Targeted patient populations Until trials include these traits, it will remain unclear which patients will benefit from immunonutrition.

AUTHORS’ RECOMMENDATIONS • Trauma and Post-surgical patients - use Immun-Aid or Impact - initiate within 24 hours of trauma or surgery - advance to goal tube feed rate within 48 hours - avoid use in septic patients • ARDS patients - use Oxepa or Pulmocare - initiate within 6 hours of diagnosis - use in septic or non-septic patients • Burn patients - glutamine may have benefit

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