Immunonutrition: problematic or problem solving?

¹ From the Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.

² Supported by a grant from the American Liver Foundation (to KCM).

³ Address reprint requests to BR Bistrian, Beth Israel Deaconess Medical Center, West Campus, 1 Deaconess Road, Boston, MA 02215. E-mail: bbistria{at}caregroup.harvard.edu.

ABSTRACT  
The addition of immune-modulating nutrients to enteral formulas has been examined in clinical trials and meta-analyses. Enhancing immunity through diet is generally done by adding n-3 fatty acids, arginine, and nucleotides to an otherwise nutritionally complete formula. Despite flaws in many studies, a consistent trend to reduced infectious complications has been seen with immunonutrition, especially in patients undergoing surgery for upper gastrointestinal cancer or trauma. In critical care populations, however, the results have been mixed. In this review, we analyze these studies and focus on select clinical points that may explain the variation. One common flaw has been a failure to deliver an adequate nutrition volume. Few patients, especially in the earliest studies, received even close to goal feeding. A minimum quantity of immunonutrition may be required for effective reduction in infections. When feeding volumes are low, immunonutrition is usually not better than an isonitrogenous control. In more recent studies, practitioners have been increasingly aggressive with enteral feeding, and this has been reflected in improved outcomes from immunonutrition. Early delivery of immunonutrition (preoperatively in surgical patients with cancer) might be particularly beneficial. Another consideration is illness severity: we discuss evidence that the use of immunonutrition in moderate illness is more likely to be helpful, whereas severe sepsis is probably beyond the reach of any nutritional intervention, and mild illness is more likely to improve irrespective of feeding. If future trials can consider these vital points, level 1 recommendations in favor of immunonutrition might be justified, although presently such evidence is lacking for most clinical indications.

Key Words: Immunonutrition • fish oil • arginine • nucleotides • enteral nutrition

INTRODUCTION  
The field of nutrition support therapy has undergone a transformation since its conception. Originally, artificial feeding was recommended as a means of providing energy, protein, and essential micronutrients to offset muscle wasting and prevent starvation-induced immune depletion. Subsequently, various dietary components have been used in an attempt to modulate immune function. To this end, specific amino acids, long-chain fatty acids, and nucleic acids have been studied. Although the composition of nutrition therapy can influence host defense, the published literature is divided on the effectiveness of manipulating nutrition support formulas to achieve hard clinical endpoints. Before considering the utility of immune-enhancing formulas, which are generally studied in comparison with standard enteral formulas, one must be convinced that enteral nutrition compared with no nutrition support at all is beneficial in a particular group of patients. The literature is replete with trials in which enteral or total parenteral nutrition was compared with saline, showing no benefit for the fed group, leading to the erroneous impression that nutrition support is ineffective or potentially harmful (1). If the patient population enrolled includes well-nourished individuals, feeding is unlikely to confer an additional benefit above that of hydration (2). Similarly, any attempt to examine potential benefits of immunonutrition in such a population might be anticipated to fail (3). The exception to this might be in severe trauma patients who are usually well nourished at admission but in whom malnutrition is likely to develop if the hospital course is protracted.

Unfortunately, the published literature examining the effectiveness of immunonutrition is beset with controversy and conflicting results. In studies from different research groups, various nutritional formulas have been used, making direct comparisons problematic. Attempts to resolve the muddle through meta-analysis have not been definitive, with somewhat different conclusions drawn from the 3 different data sets (4–6). Given that it is extraordinarily difficult to prove that any nutrition support is beneficial in comparison with intravenous fluid in most patients, proponents of the use of immune-modifying formulas have an onerous task. Overwhelming sepsis portends a grim prognosis, which is unlikely to be altered substantially by substituting one form of nutrition for another. Attempting to modulate the immune system in such a patient population probably requires the use of stronger ammunition, such as drugs or antibodies that block cytokine production or action (7). Therefore, it is in vulnerable patients (those with underlying malnutrition) with less life-threatening illnesses that nutrition support (and by inference immune-enhancing nutrition in particular) is most likely to improve outcome.

In this article, rather than present another exhaustive review of the literature, we will focus on a few critical clinical points. First, we will consider the actions of the individual components (Table 1) of the immunonutrition formulas that have been most commonly used in the published trials. Second, we will discuss the available literature on immunonutrition, examining hard clinical endpoints rather than laboratory test abnormalities. We will also focus on the relevance of both severity and type of illness and the underlying nutritional status of the patient. Then, we will address the notion that both the quantity and the timing of the immunonutrition formula ingested are important. We suspect that failure to deliver an adequate volume of feeding may account for some of the negative results. However, it is clear that large, high-quality controlled trials with appropriate randomization and aggressive feeding goals carried out in patient populations that are most likely to benefit are needed to convince the cynics that immunonutrition is safe, cost-effective, and can benefit both morbidity and mortality.

View this table:
TABLE 1 . Main constituents of immunonutrition formulas most commonly used in clincal trials¹  

CONSTITUENTS OF IMMUNONUTRITION  
The most popular formulas that have been studied in this context are Impact (Novartis Nutrition, Minneapolis) and Immun-Aid (B Braun, Irvine, CA). The important clinical similarities and what distinguishes these formulas from traditional enteral feeds is the inclusion of substantial amounts of arginine, n-3 fatty acids, and nucleotides (Table 1). It is not clear which constituents are most responsible for the immune-enhancing aspect of the solution because the components have generally not been rigorously and independently tested in large trials. In human studies, some authors have examined markers of immune function as a surrogate for definitive clinical outcomes. Activated T lymphocytes, interferon , and natural killer cells were increased in patients treated with an immune-enhancing formula compared with a control formula (8, 9). Immunoglobulin M and immunoglobulin G concentrations were also higher in the experimental group (8). Polymorphonuclear leukocyte phagocytosis and respiratory burst were enhanced in 2 studies (9, 10); in another, increased numbers of lymphocytes and percentages of T helper cells were noted (11). Postoperative interleukin 6 and tumor necrosis factor were reduced by the use of experimental immunonutrition (9).

Arginine is considered to be a conditionally essential amino acid, in that endogenous synthesis may be limiting during illness, and thus is a major component of most commercial immunonutrition formulas. Supplementation with arginine in human trials of postoperative patients results in beneficial effects on T cells (12) and wound healing (13, 14). Use of immunonutrition solutions with arginine concentrations of 6 g/L (2% of energy) has generally led to negative results (15, 16), whereas the use of solutions containing arginine in amounts > 12 g/L (> 4% of energy) often gave positive results. Addition of arginine alone as a supplement to enteral nutrition was not beneficial in a study of patients in a medical intensive care unit (ICU) (17). No human studies have shown that addition of nucleotides to the diet of humans might be beneficial, although nucleotides are plentiful in breast milk and are perhaps immunomodulatory in infants. Studies in rodents have shown enhanced immune responses to fungal challenge with the addition of nucleotides to the diet (18).

The reason for the inclusion of n-3 polyunsaturated fatty acids (PUFAs) is more readily apparent. Such fatty acids are the precursors of eicosanoids, including prostaglandins, prostacyclins, thromboxanes, and leukotrienes. A modern Western diet, and thus the cell membranes of those who eat such a diet, is relatively rich in n-6 PUFAs. Linoleic acid (18:2n-6; the essential fatty acid that ultimately gives rise to arachidonic acid, or 20:4n-6) is potentially proinflammatory by leading to increased production of interleukin 1, tumor necrosis factor , and interleukin 6, which increase eicosanoid production (19). Addition of n-3 PUFAs limits this proinflammatory effect: n-3 PUFAs inhibit both ⁶-desaturase and ⁵-desaturase, the former being rate limiting in the conversion of linoleic acid to arachidonic acid (Figure 1). In addition, n-3 PUFAs replace n-6 PUFAs in cell membrane phospholipids, which is associated with the production of prostaglandins and leukotrienes (3- and 5-series) with reduced proinflammatory potential. Therefore, n-3 fatty acids, which are included in the main commercial formulas that are available for immunonutrition and which are readily transferred from the diet into cell membranes, are antiinflammatory. Interestingly, in healthy persons, n-3 PUFAs have limited effects on eicosanoid production. n-3 PUFA are likely to be key components of immunonutrition, and are crucial to dampen any inappropriate proinflammatory effect of the added arginine in the solution.

View larger version (23K):
FIGURE 1. . Pathways of essential fatty acid metabolism from n-3 and n-6 precursors. D6D, ⁶-desaturase; D5D, ⁵-desaturase; E, elongase.

 
A few studies that have used n-3 fatty acids in enteral nutrition formulas have shown benefit. Kenler et al (20) incorporated n-3 fatty acids into a fish oil–structured lipid in postoperative gastrointestinal cancer patients and compared this with a control nutrition formula. Although not designed as an intention-to-treat study and length of stay was equal, in the subset of patients tolerating 40 mL/h, the fish oil–treated group had greater gastrointestinal tolerance of nutrition than did the control group. Gadek et al (21) enrolled ICU patients with acute respiratory distress syndrome and reported a shorter ventilator time and reduced infection rate in the group randomly assigned to receive fish oil, although this was given in combination with an n-6 PUFA, -linolenic acid. However, the use of eicosapentaenoic acid (a major n-3 PUFA present in nutritional formulas) would direct the metabolism of -linolenic acid toward di-homo--linolenic acid, which is a precursor of the 1-series eicosanoids (less inflammatory), rather than toward arachidonic acid. Gogos et al (22) randomly assigned cancer patients to n-3 supplements or placebo and showed improved ratios of T helper to suppressor cells and normalization of lowered tumor necrosis factor concentrations in the malnourished subgroup given fish oil. However, the power of the antiinflammatory effect of n-3 PUFAs alone is substantially weaker than is likely required to combat serious illness. In addition, in certain clinical situations the use of purely antiinflammatory strategies might be counterproductive, thus requiring randomized clinical trials with immunonutrition to first prove no harm.

IMMUNONUTRITION IN TRAUMA PATIENTS  
More than most patient groups, trauma patients are likely to be well-nourished at the time of hospital admission. In those with severe injury, early enteral nutrition is recommended to reduce subsequent infection (23), mainly because the duration of a significant systemic inflammatory response is likely to be prolonged. Therefore, the trauma patient population presents a good opportunity to examine immunonutrition compared with standard enteral feeding. Most studies involving randomization between an immune-enhancing formula and an appropriate isonitrogenous control have limited sample sizes. The only large study (24) unfortunately used an inappropriate low-protein control formula and thus does not address the question of whether an immune-enhancing formula is superior to isonitrogenous "regular" feeding. Viewed as such (Table 2), the data are not overwhelmingly in favor of immunonutrition, although they do suggest benefit. The only 2 well-controlled trials [those by Mendez et al (16) and Kudsk et al (25)] had radically different outcomes, one positive and the other negative for reductions in infectious complications. The major difference was that the positive trial used an experimental formula that contained substantially less arginine (6.6 compared with 14 g/L) and did not contain nucleotides, raising the consideration that the exact constituents of the feed may be of paramount importance. Overall, the studies in Table 2 should prompt us to attempt a trial that is both well controlled and sufficiently powered to address this question.

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TABLE 2 . Summary data (intention-to-treat analysis) of trials of immunonutrition in trauma patients¹  

IMMUNONUTRITION IN GASTROINTESTINAL CANCER SURGERY PATIENTS  
The second group in which benefit from immunonutrition might be anticipated is patients undergoing elective surgery for upper gastrointestinal or pharyngeal cancer (Table 3). Underlying malnutrition renders this population vulnerable to infectious complications. Preoperative total parenteral nutrition for 1 wk in gastrointestinal cancer patients with weight loss was shown to reduce postoperative infections (43). A recent study by Braga et al (27) focused on such a population with weight losses of > 10% of body weight over the preceding 6 mo who were randomly assigned to 3 different treatments: pre- and postoperative immunonutrition, preoperative immunonutrition plus postoperative control solution, or postoperative control solution only. The group receiving immunonutrition both before and after surgery had fewer complications than did those fed control solution postoperatively. Although the statistical analysis did not confirm this, use of immunonutrition both before and after surgery in malnourished patients showed a trend toward being the best treatment. The only other authors to consider the most malnourished patients separately were Riso et al (11). In this study of head and neck cancer patients that showed no overall benefit of immunonutrition, the malnourished subgroup given this treatment compared with the control nutrition solution benefited in terms of infectious and wound complications.

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TABLE 3 . Summary data (intention-to-treat analysis) of trials of immunonutrition in surgical patients with gastrointestinal or head and neck cancer¹  
When the outcomes of the listed trials of immunonutrition in gastrointestinal cancer (Table 3) are examined, substantial flaws are evident in study design. The largest studies (40, 41) were not intention-to-treat analyses in the entire fed population because those intolerant of 3 L after the randomization step were not examined further. The other group enrolling large numbers of patients with gastrointestinal cancer was that of Braga and Gianotti. Many of the studies published by these authors, however, may be composed of the same patients. This group has published 2 main protocols other than that mentioned above: either preoperative + postoperative nutrition (immunonutrition compared with control) (34, 35) or a postoperative feeding only strategy (immunonutrition compared with control) that included a total parenteral nutrition comparison group (28–33). It appears that each new publication may represent an analysis of one subpopulation of their patients or be a reanalysis with additional patients. This is particularly worrying because this fails to allow a careful evaluation of outcomes. The most recent publication from this group was a randomized controlled trial of immunonutrition compared with intravenous fluids in patients who were not significantly malnourished at enrollment and who had not been included in any prior publication (38). Two immunonutrition substudies were performed: preoperative x 5 d only and both preoperative and postoperative. A significant benefit of immunonutrition for postoperative infections and length of stay was found in both substudies. The flawed studies included, Table 3 suggests a benefit of immunonutrition for infectious complications in upper gastrointestinal cancer patients undergoing surgery.

IMMUNONUTRITION IN INTENSIVE CARE PATIENTS  
The patient group in which the most doubt exists as to risk versus benefit of immunonutrition is the ICU population (Table 4). Heterogeneity of patients is likely to be greater here than in gastrointestinal cancer or trauma; thus, varied results should not be surprising. Three large studies of ICU patients have been published (44–46), although one (46) used an inappropriate control solution that provided less protein. In that particular study, there were more deaths in the immunonutrition group (NS) and no benefits to immunonutrition in the intention-to-treat analysis. Immunonutrition reduced mortality in a second study (44), whereas the third (and largest) (45) found no difference from control in the intention-to-treat analysis. Thus, it is difficult to recommend immunonutrition in this patient population. Close reading of the 2 studies with an appropriate control nutrition formula (44 and 45) reveals a potential reason for the conflicting results: quite different proportions of patients were successfully fed in the 2 studies. Successful feeding was defined in the former study as > 833 mL/d, attained in only 26% of participants. The study did not show any benefit of immunonutrition in the intention-to-treat analysis (although the well-fed 26% did show marked benefits when compared with the similarly fed controls). In contrast, extrapolation of the data given in the paper of Galban et al (44) suggests that 84% of patients received > 820 mL/d, and here immunonutrition reduced mortality.

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TABLE 4 . Summary data (intention-to-treat analysis) of trials of immunonutrition in intensive care unit (ICU) patients¹  
In the inappropriately controlled ICU study of Bower et al (46), even though negative overall, a reduction in length of stay with immunonutrition compared with the low-protein control feed was found in the group that tolerated > 821 mL/d (possibly those who were less critically ill). It is not clear whether the calculation for length of stay considered the number of deaths (greater with immunonutrition, although not significantly so).

A subgroup of ICU patients, those with burns, was examined in 2 studies of immunonutrition (47, 48). In only one study were control subjects assigned to an appropriate control formula, and this study showed no benefit of immunonutrition over usual enteral feeding.

An alternative explanation for the ineffectiveness of immunonutrition in some ICU studies is that the patient population is so ill that no dietary manipulation can be sufficiently powerful to alter the course of disease. Interestingly, in the study of Galban et al (44), the subgroup that benefited most from the intervention was that with APACHE (acute physiology and chronic health evaluation) scores of 10–15. Our reanalysis of their data showed that the subgroup with APACHE scores of 10–20 saw benefit, whereas the subgroups with higher APACHE scores showed no significant improvement with Impact. In the study by Bower et al (46), a septic subgroup with an average APACHE score of 16 also showed benefit for immunonutrition compared with control.

QUANTITY AND TIMING OF IMMUNONUTRITION  
An accumulating body of evidence suggests that unless immunonutrition can be delivered sufficiently in advance of surgical insult, the benefits are unimpressive. This may be an extension of the finding discussed above in ICU patients that 800 mL/d is required to maximize outcome from immunonutrition. The effect of duration is most clearly appreciated in the trial of Braga et al (27), in which malnourished surgical patients were randomly assigned to receive 1 L of either immunonutrition formula or isonitrogenous control solution for 7 d (per os) before surgery in addition to for up to 1 wk postoperatively through a jejunostomy tube. Clear advantages were seen in the intention-to-treat analysis in the experimental group, who had reductions in infectious complications. This finding is most impressive when contrasted with other trials in surgical patients (Table 3) in which the results of many of the intention-to-treat analyses were negative.

The importance of the duration, quantity, and timing of immunonutrition is similarly emphasized in 2 large studies from the same group discussed previously of gastrointestinal cancer patients undergoing laparotomy (40, 41) and assigned to immunonutrition or isocaloric and isonitrogenous formula. In the first study of 164 patients randomly assigned to postoperative immunonutrition or a control diet, no significant difference in complications was seen between the groups (40). However, in hypothesis generation from subgroup analyses, it was shown that late (after day 5) postoperative complications were reduced in the Impact-treated patients. Therefore, in the second study by this group (41), patients were randomly assigned to receive pre- and postoperative nutrition therapy, either immunonutrition or an appropriate control, and the total number of complications was shown to be reduced by immunonutrition. Unfortunately, in neither of these studies were the results presented as an intention-to-treat analysis; thus, these studies do not represent the final word on this issue.

In the only study to examine patients undergoing cardiac surgery, participants were randomly assigned to drink 5–10 L of either immunonutrition or a control enteral feeding solution over the 5–10 d before surgery (49). The control solution was relatively lower in protein, unfortunately, and the study was not analyzed as intention-to-treat. However, the secondary endpoint of new postoperative infections was significantly reduced in the immunonutrition-treated group, related mainly to fewer cases of pneumonia. The consequences of this were that vasopressor use and renal failure were significantly lower. Primary endpoints in this study were laboratory and clinical markers of host defense (delayed hypersensitivity response to antigens), which were also improved in the treatment group.

These data from Braga et al (27) and Senkal et al (40, 41) suggest either that substantial amounts of the supplements must be absorbed before an effect is evident or that the timing of use of immunonutrition is key. One interpretation of this finding is that the most critical change to be made to feeding policies is to become more aggressive in trying to reach enteral goals and in trying to feed malnourished patients preoperatively. It is possible that research dollars would be better spent tackling this problem than being used to fund yet another inconclusive trial of immunonutrition compared with a control formula. Interestingly, the results of recently published enteral feeding studies have shown that the use of aggressive protocols is associated with high rates of attainment (> 90%) of goal feeding rates (50). On a background of greater numbers of patients being fed appropriately, immunonutrition might be more likely to show benefit.

SUMMARY  
The available literature suggests that in trauma and perioperative patients immunonutrition may reduce the number of infectious complications. However, the results of most trials have been negative for important outcomes such as mortality. In the larger trials, intention-to-treat analyses of the effectiveness of immunonutrition have also been mostly negative. If it is possible to provide immune-modifying nutrition support early in the course of illness and to give it in rather large amounts, its benefits are more easily detected. In acutely ill general ICU patients, there appears to be no overall benefit, although, interestingly, this may reflect the degree to which the patients receive the assigned feeding. Across all studies, there was a trend to a lower infection rate. In general, the greatest flaw in most of the published trials has been underfeeding. Common to the 3 meta-analyses was the universal finding of shorter hospital length of stay and an overall reduction in numbers of infectious complications. We conclude that, as physicians and nurses grow increasingly skilled at reaching and maintaining goal feeding rates with enteral nutrition, the benefits of immunonutrition are more likely to be realized and may ultimately be proven cost-effective.

In summary, the current data suggest that immunonutrition should be considered in the following patients: 1) patients undergoing abdominal surgery for cancer, especially malnourished patients (both preoperatively and postoperatively); 2) ICU patients with APACHE scores of 10–20 but not higher; and 3) patients with multiple trauma. Practical strategies to maximize the success of these formulas are as follows: 1) arginine should be > 12 g/L (found in Impact or Immun-Aid); 2) duration should be > 3 d, preferably 5–10 d; 3) nasogastric feeding should be used aggressively, with nursing protocols to advance feeding every 4–6 h, and gastric residuals of 200 mL should be accepted; and 4) feeding goals should approach 25 kcal/kg, and 800 mL/d should be given for optimum outcome.

ACKNOWLEDGMENTS  
BRB receives royalty payments from Novartis and Ross Products Division of Abbott Laboratories related to fish oils.

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