Immunonutrition and critical illness: An update

Nutrition 26 (2010) 701–707

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Review

Immunonutrition and critical illness: An update Barry A. Mizock M.D., F.A.C.P., F.C.C.M. * Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 17 June 2009 Accepted 5 November 2009

Dietary supplementation with nutrients that have physiologic effects on immune function has been shown to be beneficial in subsets of patients with surgical and medical critical illness. However, several meta-analyses have suggested potential harm when immune nutrients are used inappropriately. This has led to concern among clinicians that in turn has curtailed the more widespread use of immunonutrition as a therapeutic modality. This article discusses the mechanisms by which immune nutrients can be used to modulate alterations in innate and acquired immunity associated with critical illness. In addition, recent evidence-based clinical practice guidelines for use of immunonutrition in adults is reviewed as a means to clarify some of the more controversial issues and provide a ‘‘roadmap’’ for the practitioner. Ó 2010 Elsevier Inc. All rights reserved.

Keywords: Immunonutrition Omega-3 fatty acids Fish-oil Glutamine Arginine Antioxidants Critical illness

Introduction The concept of immunonutrition (nutritional immunology) evolved from the realization that optimal function of the immune system is impaired in the presence of malnutrition [1]. The evolution of immunonutrition as a therapeutic modality was stimulated by Alexander’s pioneering work in burn injury. His research led to the development of the Shriners burn formula, an enteral feeding solution supplemented with immune nutrients (e.g., arginine, omega-3 fatty acids, vitamins A, C, and zinc). This formula reduced wound infection and length of stay in burned patients [2]. In 1992, Daly and colleagues studied the efficacy of an immunonutrient formula supplemented with arginine, omega-3 fatty acids, and nucleotides on clinical outcome in postoperative patients who had undergone major elective surgery for upper gastrointestinal malignancy [3]. When compared to patients receiving a standard enteral diet, patients who received the immune formula had a decrease in wound and infectious complications, as well as a more rapid restoration of lymphocyte mitogenesis. Subsequently, a large number of clinical trials have been conducted utilizing various proprietary immune formulas in subgroups of critically ill patients. Positive effects included the following: reduced infectious complications, shorter time on the ventilator, reduced hospital and intensive care unit (ICU) length of stay, and reduced mortality. However, not all studies yielded positive results, with several indicating * Corresponding author. Tel.: þ312-413-5449; fax: þ312-413-8283. E-mail address: [email protected] (B. A. Mizock) 0899-9007/$ – see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2009.11.010

potential harm, notably in patients with underlying sepsis. In addition, delivery of immune nutrients as a constituent of a nutritional formula may be limited in patients with gastrointestinal intolerance who cannot attain target infusion rates. This in turn stimulated the approach of ‘‘pharmaconutrition,’’ which involves administering immune nutrients dissociated from the provision of calories and protein [4]. This article is not intended to be a comprehensive discussion of clinical studies of immunonutrition, and the reader is referred to several excellent reviews [5-7]. Instead, this article utilizes recent evidence-based clinical practice guidelines to provide a ‘‘roadmap’’ by which the clinician can most effectively utilize immunonutrition to improve outcome in adult critically ill patients. This discussion is preceded by concise summaries of the characteristic alterations in innate and acquired immune accompanying critical illness and the mechanisms by which immune nutrients can favorably impact the immune response. Immune alterations in critical illness The term ‘‘critical illness’’ can be defined as ‘‘a life-threatening medical or surgical condition usually requiring ICU-level care that includes, but is not limited to, trauma, surgery, sepsis, shock, and severe burns’’ [7]. However, the immune status of critically ill patients is by no means homogenous, and these patients have significant differences in underlying immune status that precludes their being ‘‘lumped’’ together [8,9]. This in turn dictates variations in the immune nutrient profile that is appropriate for each group.

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Both innate and acquired immunity are involved in the response to acute severe illness. The innate immune response is characterized by an initial local inflammatory reaction at the site of infection or injury, which involves activation of macrophages and monocytes, the alternate complement pathway, and the blood coagulation system. The local inflammatory reaction is amplified through the release of pro-inflammatory mediators (e.g., tumor necrosis factor, interleukin-1, prostaglandins, leukotrienes, thromboxanes) that in turn leads to the systemic inflammatory response syndrome (SIRS). The initial phase of the SIRS response is felt to be an adaptive process that facilitates resolution of the acute inciting process. However, a maladaptive response secondary to overwhelming or prolonged systemic inflammation (e.g., ‘‘excessive SIRS’’) may ensue as the result of factors such as the type of infecting organism, genetic predisposition to overexpression of inflammatory cytokines, patient age, and comorbidities [10]. Clinical syndromes associated with excessive SIRS include the following: the acute respiratory distress syndrome (ARDS), septic shock, disseminated intravascular coagulation, and the multiple organ dysfunction syndrome. The mechanism for organ dysfunction in the setting of systemic inflammation appears to involve extensive mitochondrial damage resulting from overproduction of nitric oxide and its metabolite peroxynitrite [11]. Provision of supplemental arginine in the setting of severe sepsis (especially with multiple organ dysfunction) may be deleterious in this regard by further augmenting production of nitric oxide [8] (see below). The adaptive immune response develops several days after the initial innate response and involves the interaction between antigen-presenting cells (e.g., macrophages, dendritic cells) and lymphocytes that are responsible for cell-mediated immunity and antibody production. A transient downregulation of adaptive immunity is commonly seen in patients with acute critical illness that is termed the ‘‘compensatory anti-inflammatory response syndrome’’ (CARS) [12]. The CARS response may have evolved as a means to prevent downstream damage to distant organs by locally produced inflammatory mediators [13,14]. The components of the CARS include both cellular/molecular elements (e.g., lymphocyte dysfunction and apoptosis, monocyte/macrophage deactivation, increased production of interleukin-10) and clinical elements (e.g., cutaneous anergy, hypothermia, leukopenia) [13,14]. In patients who have sustained significant trauma or following major surgery, upregulated arginase expression in granulocytes results in a decrease in plasma arginine levels [15–17]. The resultant arginine-deficient state suppresses the acquired immune response by decreasing translation of the zeta-chain peptide on the T-cell receptor complex [15]. In certain patients (e.g., following major trauma) a maladaptive state of profound, prolonged immunosuppression (‘‘immunoparalysis’’) may develop that is associated with increased risk of nosocomial infection, organ dysfunction, and death [18]. In summary, critical illness may be accompanied by various combinations of systemic inflammation and generalized immunosuppression. Both of these conditions are amenable to therapy with pharmaconutrients. Antioxidant vitamins and trace elements Endogenous antioxidants play an important role in minimizing cellular damage resulting from enhanced production of reactive oxygen and nitrogen species (e.g., oxidative stress) [19]. The endogenous antioxidants have been collectively termed the antioxidant defense system [19]. The antioxidant defense system

includes enzymes (e.g., superoxide dismutase, glutathione peroxidase), trace elements (e.g., selenium, zinc), vitamins (e.g., vitamin C, E, beta-carotene), sulfhydryl group donors (e.g., glutathione), and glutamine. Critical illness is associated with deficits in circulating antioxidants due to the following: 1) a SIRS-induced redistribution from blood to tissues; 2) increased losses (e.g., during burn or trauma); 3) decreased nutritional intake [19]. The resultant reduction in antioxidant potential promotes increased cellular oxidative injury (especially lipid peroxidation). A number of clinical studies have explored the potential benefit of supplementation with antioxidants. The combinations and doses of antioxidants varied considerably. Heyland et al. performed a meta-analysis of clinical studies of trace element and vitamin supplementation in critically ill patients. They concluded that trace elements and vitamins that support antioxidant function, particularly high-dose parenteral selenium (either alone or in combination with other antioxidants), are safe and may be associated with a reduction in mortality [20]. However, the optimal combination and doses of micronutrients remain to be determined. Macronutrients Glutamine Glutamine is the most abundant free amino acid in the body, with skeletal muscle glutamine constituting greater than 50% of the total free amino acid pool. Muscle stores of glutamine become rapidly depleted in catabolic stress states (e.g., trauma, sepsis, burn), and glutamine can therefore be considered conditionally essential in this setting. Mobilization of glutamine provides substrate for gut, immune cells, and kidneys. Beneficial effects of glutamine include the following: anti-oxidant effects (as a precursor of glutathione), inducing production of heat shock proteins, maintaining gut barrier function by providing fuel for enterocytes, as an energy substrate for lymphocytes and neutrophils, and stimulation of nucleotide synthesis [21]. Novak et al. performed a meta-analysis of glutamine supplementation in serious illness [22]. They found that in elective surgical patients, glutamine reduced infectious complications and length of hospital stay, without adverse effects on mortality. Positive results were also seen in critically ill patients, in whom supplemental glutamine reduced complications and mortality rates. The greatest effects were observed with high-dose (>0.20 g/kg/ d) parenteral glutamine. Unfortunately, the optimal parenteral preparation of glutamine (L-alanyl-L-glutamine dipeptide) is not available in the US, and supplementation must therefore be provided enterally (usually with glutamine powder). Alternately, some immunonutrient formulas contain a glutamine equivalent (e.g., hydrolyzed wheat protein). A study in healthy human volunteers indicated that the bioavailability of a glutamine equivalent (oat protein concentrate) was similar to enteral glutamine given as a free amino acid [23]. However, it is unclear whether the bioavailability of a glutamine equivalent is similar in patients who are critically ill. A recent trial in postoperative patients found that an arginine-supplemented immuneenhancing diet increased plasma glutamine, possibly by enhancing de novo synthesis from arginine [24]. Arginine Arginine is also conditionally essential during certain types of critical illness (e.g., trauma, postoperative). Beneficial effects of arginine supplementation include the following: 1) secretegogue

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for release of anabolic hormones (e.g., growth hormone, insulinlike growth factor); 2) supporting immune (especially T-cell) function; 3) detoxification of ammonia; 4) improving wound healing via metabolism to polyamines and proline [8]. An arginine deficiency syndrome commonly develops following severe trauma or major surgery that is mediated by pathologic release of arginase from granulocytes [15,17]. Arginine deficiency impairs the acquired immune response by causing T-cell receptor (zeta chain) abnormalities; this in turn increases predisposition to nosocomial infections, and impairs wound healing [15,16]. In this setting, provision of supplemental arginine helps to reverse the immunosuppressed state. Concomitant supplementation with fish oil is also beneficial in restoring T-cell function by inhibiting arginase, thereby increasing the available arginine [25]. Plasma levels of arginine during sepsis are variable depending on the stage at which they are measured. Arginine deficiency is most likely to be present in the earlier stages of sepsis, although not as severe as seen following major trauma [26]. In contrast, plasma arginine levels increase progressively as the severity of sepsis worsens, particularly in the setting of multiple organ dysfunction [26,27]. Thus, the benefit of arginine during sepsis may depend on the stage at which supplementation is administered; patients with more severe metabolic decompensation would be less likely to benefit and could potentially be harmed (see below). This hypothesis could account for the findings of a study that observed greater beneficial effects of an arginine-supplemented immune formula in septic ICU patients with less severe disease (Apache II <15) [28]. In 2001, Heyland and Novak published a meta-analysis of arginine-supplemented immune-enhancing diets in critically ill patients, in which they noted evidence for adverse effects on outcome [29]. These ‘‘danger signals’’ were seen mainly in nontrauma patients who were infected at the baseline. Although this analysis was not designed to uncover a precise mechanism for these harmful effects, the authors felt that supplementation of arginine in the setting of sepsis could be responsible. This hypothesis was based in large part on data from three studies that showed worsened outcome in septic patients who were administered an arginine-supplemented immunonutrient solution (compared to those receiving a standard formula) [30–32]. A subsequent similar meta-analysis concluded that although beneficial effects of arginine supplementation in surgical patients were consistently seen (e.g., reduction in infectious risk, decreased ventilator and ICU days, decreased hospital stay), critically ill patients did not benefit and may even have been harmed [33]. A 2008 meta-analysis of immunonutrition in critically ill patients found that the addition of arginine to fish oil appeared to counteract the benefits of fish oil on outcome of ICU and trauma patients with sepsis/SIRS [9] (Fig. 1). The mechanism for potential adverse effects of arginine in severe sepsis is unknown but could involve a cytokine-mediated induction of the type 2 isoform of nitric oxide synthase. Once this enzyme is induced, nitric oxide production is dependent largely on availability of arginine. Therefore, provision of supplemental arginine in severe sepsis could promote the generation of large quantities of nitric oxide that are subsequently metabolized to peroxynitrite [34]. This molecule is a potent oxidant and nitrating agent that damages mitochondria, increases gut barrier permeability, and promotes organ dysfunction [34–36]. In summary, postoperative and trauma are typically argininedeficient states, and these patients consistently benefit from arginine supplementation. However, critically ill medical patients exhibit little if any benefit, and a strong possibility of increased mortality exists when arginine is supplemented

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Fig. 1. Odds ratio (with 95% confidence interval) of the treatment effect (for two or more studies) of the immunonmodulating diets on mortality. Arg, arginine; A-FO, arginine þ fish oil, FO, fish oil; AFG, arginine þ fish oil þ glutamine; Gl, glutamine. Used with permission [9].

during severe sepsis and multiple organ dysfunction syndrome (Fig. 2). Fish oil and gamma-linoleic acid Cold-water fish (e.g. sardines, mackerel, tuna) are rich in eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), the active metabolites of alpha-linolenic acid (ALA). The high EPA/ DHA content of fish results from dietary intake of a food chain that includes phytoplankton. Although marine plankton can efficiently metabolize ALA to EPA and DHA via desaturase enzymes, humans possess a limited capacity to synthesize EPA and DHA during basal conditions (only 8% of dietary ALA is converted) [36]. During acute, severe illness, these desaturases are markedly downregulated so that EPA and DHA synthesis from ALA is negligible. Therefore, supplementation of omega-3 fatty acids in critically ill patients requires administration of fishoil-based lipids. Mechanisms for the anti-inflammatory action of EPA and DHA include the following: 1) displacing arachidonic acid (AA) from the phospholipid core of the inflammatory cell (e.g., macrophage, neutrophil) membrane, thereby reducing synthesis of pro-inflammatory eicosanoids; 2) reduction in synthesis of pro-inflammatory eicosanoids by competing with AA for metabolism by the enzymes cyclooxygenase and lipoxygenase; 3) reducing leukocyte and platelet adhesive

Fig. 2. Benefit versus harm of arginine-supplemented immune-enhancing diets (IED). Patients undergoing elective surgery benefit from the use of IED, exhibiting a significant decrease in infection rates. Trauma patients may benefit, but only if they receive adequate amounts of an IED early after their injury. Medical patients appear to exhibit little if any benefit. Medical patients with severe sepsis exhibit little benefit; potential for increased mortality. Used with permission [16].

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interaction with the endothelium; 4) inhibition of inflammatory gene expression; 5) reduction of oxidative injury by stimulating glutathione production; 6) enhancing synthesis of antiinflammatory resolvins; 7) a lung-protective effect mediated by reducing the release of gut-derived inflammatory mediators into mesenteric lymphatics and thoracic duct [37–39]. Gamma linolenic acid (GLA) is an omega-6 polyunsaturated fatty acid (derived from borage oil) that has a synergistic effect with EPA and DHA in reducing lung inflammation [37,40]. In addition, GLA is ultimately metabolized to one-series prostaglandins (e.g., PGE1) that promote pulmonary vasodilation; this in turn helps to counteract the excessive pulmonary vasoconstriction that occurs in patients with acute lung injury (ALI) and ARDS [41]. Positive effects of an immunonutrient formula containing fish oil, borage oil, and antioxidants on mechanically ventilated patients with ALI or ARDS were documented in three major randomized clinical trials [42–44]. Significant reduction in duration of ventilation, ICU and hospital stay, and incidence of new organ failure was seen. Two of the studies also showed a reduction in 28-d mortality in the treatment group [43,44]. A meta-analysis combined the results of the three aforementioned trials (411 total patients) and found a 49% reduction in intentionto-treat mortality, with the number needed to treat to save an additional life at day 28 equal to five [45]. Two additional trials investigating nutritional supplementation in ALI/ARDS are currently in progress. The ‘‘Fish Oil Study’’ is designed to compare the effects of enteral administration of pharmaceutical grade fish oil (8 g/d divided every 6 h) versus placebo on mortality, ventilator-free days, ICU and hospital length-of-stay, and infections. The study was completed in December 2008, and results are pending. The ARDSnetsponsored ‘‘EDEN-OMEGA’’ study was conducted to compare early versus delayed full-calorie feeding on ventilator-free days and survival rates. This study was also designed to determine the benefit of a twice-daily modular administration of fish oil, borage oil, and antioxidants versus placebo on these clinical outcomes. Unfortunately, the immunonutrient (‘‘OMEGA’’) arm of the study was terminated due an interim statistical analysis that suggested that the primary endpoint (ventilator-free days) could not be achieved if the study continued to completion. The relevance of

this data to clinical practice is unclear since the immune response to modular administration of pharmaconutrients may be dissimilar to that of the immunonutrient formula containing fish oil, GLA, and antioxidants. Clinical use of immunonutrition during critical illness Selection of the most appropriate immunonutrient formula should ideally be directed by laboratory testing that would enable rapid and accurate assessment of the patient’s immune status. Since clinicians lack an ‘‘immunometer,’’ nutritional decision-making is typically guided by the patient’s diagnostic category in conjunction with relevant practice guidelines. Three evidence-based clinical practice guidelines for nutritional support of critically ill patients have recently been published: 1) the Canadian Clinical Practice Guidelines (CCPG) for nutritional support in mechanically ventilated critically ill adults (updated in 2009); 2) the European Society for Parenteral and Enteral Nutrition (ESPEN) guidelines on enteral nutrition in intensive care (published in 2006); 3) the Society of Critical Care Medicine and American Society of Enteral and Parenteral Nutrition (SCCM/ ASPEN) nutritional guidelines for critically ill adults (published in 2009) [46–48]. These guidelines are organized based on indications for micro- and macronutrient supplementation in various populations of critically ill patients (e.g., sepsis, burn, trauma, postoperative). The CCPG recommendations are categorized as follows: recommended, should be considered, should not be used, and no recommendation due to inadequate data. In contrast, the ESPEN and SCCM/ASPEN guidelines are graded A through D based on the level of evidence. A summary of these guidelines is presented in Table 1. ICU patients not meeting criteria for immunonutrition should receive standard enteral formulations [48]. A number of enteral products containing immunonutrients are currently available in the US and abroad. These formulas contain varying amounts of arginine, EPA/DHA, GLA, and antioxidants. Products commonly used in the US are summarized in Table 2. The term ‘‘immune-enhancing diet’’ is used to refer to enteral formulas containing supplemental arginine along with fish oil and antioxidants. As discussed above, these formulas are most appropriate for patients who are likely to

Table 1 Immune nutrients for specific patient populations: summary of clinical practice recommendations Nutrients

Elective surgery

General

Septic

Trauma

Burns

ALI/ARDS

Arginine* CCPG ESPEN

No rec Benefit (B)

No benefit No rec

No benefit Benefit (B)

No benefit No rec

No benefit No rec

Benefit (A)

Poss benefit (A)

Harm Benefit (mild) (B) Harm (severe) (B) Poss benefit (mild/mod) (B) Poss harm (severe) (B)

Benefit (A)

Benefit (A)

No rec

No rec No rec No rec

No rec No rec Poss benefit (B)

No rec No rec No rec

Poss benefit Benefit (A) Poss benefit (B)

Poss benefit Benefit (A) Poss benefit (B)

No rec No rec No rec

No rec No rec No rec

No rec No rec No rec

No rec No rec No rec

No rec No rec No rec

No rec No rec No rec

Benefit Benefit (B) Benefit (A)

No rec No rec No rec

Poss benefit No rec Benefit (B)

No rec No rec Benefit (B)

No rec No rec Benefit (B)

No rec Benefit (A) Benefit (B)

No rec No rec Benefit (B)

SCCM/ASPEN y

Glutamine CCPG ESPEN SCCM/ASPEN U-3 fatty acidsz CCPG ESPEN SCCM/ASPEN Antioxidantsx CCPG ESPEN SCCM/ASPEN * y z x

Arginine administered in context of immune-enhancing diet that also contains fish oil, antioxidants,  nucleotides. Enteral glutamine added to enteral nutrition regimen. Fish-oil-derived U-3 fatty acids (EPA and DHA) administered in context of immune-enhancing diet that also contains borage oil and antioxidants. Antioxidant vitamins (including selenium) and trace elements.

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Table 2 Enteral products containing immunonutrients

Manuf Fat

Pro (g/L) CHO (g/L) Fat (g/L) Cat/mL Arg (g/L) (% cal) EPA/DHA (g/L) U-6 FA (g/L) U-6/U-3 Osm (mOsm/kg) Vit A (IU/L) Vit C (mg/L) Vit E (IU/L) Selenium (mcg/L) Note

Crucial

Peptamen AF

Impact

Optimental

Oxepa

Peritive

Pivot 1.5

Nestle MCT Fish Soy 94 peptide 94 68 1.5 15 4% 2.8 7.7 2:1 490 15,000 1000 100 100 High ARG Cal dense

Nestle MCT Fish Soy 75.6 peptide 107 54.8 1.2 IPS

Nestle MCT Fish Sunf 56 130 28 1.0 12.5 5% 1.7 2.5 1.4:1 375 6700 80 60 100 High ARG Nucleotides

Abbott Struct lipid (Fish, MCT) Canola Soy 51.3 peptide 138.5 28.4 1.0 3.6 1.4% 3.3 6.4 0.9:1 586 8223 210 210 50 ARG Prebiotic

Abbott MCT Canola Fish Borage 62.5 105.5 93.7 1.5 IPS

Abbott MCT Canola Corn 66.7 peptide 180.3 37.3 1.3 8.0 2.5% 0 6.0 4.8:1 304 8675 260 39 63 High ARG Cal dense

Abbott Struct lipid (Fish, MCT) Canola Soy 94 peptide 172 50.8 1.5 13 3.5% 3.9 5.8 1.5:1 595 10,000 300 250 70 High ARG Cal dense prebiotic

2.4 16.7 1.8:1 390 8000 384 120 160 Cal dense prebiotic

6.6 18.8 1.75:1 493 11910 850 120 76 Cal dense GLA

No rec, no recommendation; IPS, inherent in protein source; ARG, arginine; GLA, gamma-linolenic acid; MCT, medium-chain triglycerides

be arginine-deficient (e.g., elective surgery, trauma). Bistrian and McCowen recommend that immune-enhancing formulas should ideally contain greater than 12 g arginine/L (>4% of resting energy expenditure) [36]. The optimal duration of administration is at least 3 d, preferably 5–10 d [36]. The ESPEN and SCCM/ASPEN guidelines support the use of immune-enhancing diets in patients with mild-to-moderate sepsis; however, both advise against the use of immuneenhancing diets in patients with severe sepsis. The CCPG guidelines maintain that arginine-supplemented immuneenhancing diets not be used for critically ill patients (especially with sepsis). The optimal formula for septic patients has not been defined at this point in time. The fish oil/GLA/antioxidant formula was shown to be beneficial in patients with severe sepsis or septic shock who had ALI/ARDS [44]. A Brazilian trial is currently in progress that is designed to assess the efficacy of this formula in septic patients without underlying severe lung disease. All three practice guidelines recommend the use of the fish oil/GLA/antioxidant formula in critically ill patients with ALI/ARDS. The optimal dose of EPA/DHA in patients with ALI and ARDS has not been determined. A reasonable goal would be to provide the mean daily dose administered in the clinical trials mentioned above (e.g., 7–10 g EPA/DHA/d). Enteral immune products contain varying amounts of antioxidant vitamins and trace elements. Supplementation with additional pharmaconutrients (e.g., selenium) may be desirable in certain patients. Positive effects of high-dose parenteral selenium supplementation were recently documented in patients with SIRS, sepsis, and septic shock [49]. In contrast, another trial of selenium supplementation in septic shock failed to demonstrate beneficial effects [50]. It was suggested that lack of efficacy in this study may have been due to an excessive dose of selenium [51]. Concerns regarding the safety of high doses of antioxidants (e.g., potential pro-oxidant effects) were addressed in a doseoptimizing study [52]. This trial found that supplementation with 800 mg of selenium in combination with other antioxidants and glutamine appeared to be safe and had some positive effects on physiologic function. The optimal dose of selenium during septic critical illness remains to be determined, but doses ranging between 500–750 and 800–1000 mg/d for 1–3 weeks

have been suggested [19,51]. Somewhat lower doses (e.g., 300– 500 mg/d) were recommended for major trauma and burns [53]. The REDOX study (currently in progress) is designed to evaluate the effect of antioxidant and glutamine supplementation on mortality of critically ill patients and hopefully will clarify some of these issues. The importance of early initiation of enteral feeding (e.g., within the first 24–48 h following admission) in critically ill patients was stressed by all three practice guidelines as a means to decrease infectious morbidity and hospital length of stay [46–48]. Timely administration of immunutrition is particularly important in patients with ALI or ARDS. Animal studies have suggested that it may take as long as 72 h before significant effects of EPA and GLA on the polyunsaturated fatty acid profile of inflammatory cell membranes becomes apparent (e.g., reducing AA content) [54]. In elective surgery patients, the beneficial effects of immunonutrition are most apparent when the formula is given in the preoperative period [6,48]. It is also important to aggressively advance the infusion rate as tolerated. The SCCM/ASPEN guidelines propose that at least 50%–65% of goal energy requirements should be delivered to receive optimal therapeutic benefit from immune-modulating formulas [48]. Dysfunction of the gastrointestinal tract is common in acutely ill patients and can limit the amount of immunonutrition delivered enterally [55]. ESPEN guidelines maintain that critically ill ICU patients who do not tolerate more than 700 mL of enteral nutrition/d should not receive immune-enhancing diets [47]. In mechanically ventilated patients receiving continuous infusion of propofol for sedation (especially at higher doses), the associated caloric load can be substantial (each milliliter provides 1.1 kcal) [56]. For example, an 80 kg patient infused at a rate of 60 mg/kg/min receives approximately 760 kcal per day. This in turn could be counterproductive by promoting overfeeding, as well as by limiting the amount of fish-oil-based lipids that can be administered. Other associated risks of high-dose propofol infusion include the following: increased potential for developing hyperlipidemia, adverse effects of parenteral soy-based lipids in ICU patients, and the propofol-infusion syndrome [46,48,57].

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Conclusions The value of immunonutrient formulas in the management of critically ill and postoperative patients is now acknowledged by many medical practitioners. However, it is important that the clinician be aware that ‘‘one size does not fit all.’’ This implies that the immune nutrient profile that is appropriate for the trauma or elective surgery patient may be of minimal benefit for the medical ICU patient and could be potentially harmful in the setting of sepsis. Making rational decisions in choosing the optimal formula will minimize adverse effects that currently serve to curtail the more widespread use of this valuable therapeutic modality.

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