Immune-Enhancing Nutrition in Surgical and Critical Care

Abstract

Immune-enhancing nutrition, or “immunonutrition,” refers to the use of specialized nutrients, including glutamine, alanine, omega-3 fatty acids, and others, that help regulate the body’s response to illness and injury. Clinical studies have demonstrated some very specific benefits, including fewer infectious complications and shorter length of hospitalization, in certain populations including high-risk surgical patients, trauma victims, and the critically-ill. Nationally recognized guidelines support the use of immune-enhancing nutrition in high-risk patients.

Introduction

The field of “immunonutrition” is less than 20 years old. The term refers to the use of specific nutrients that have specific effects upon the immune system. In many ways, these nutrients act as pharmacological agents. Some nutrients appear to have specific effects on the immune system, to either enhance or suppress it. In particular, there are nutrients which appear to modify the body’s response to inflammation, or to enhance the immune system in malnourished, critically-ill, or critically injured patients. Which populations of patients may benefit and which specific nutrients are most effective are both the subject of active current research. The intent of this review is to discuss the basis for using particular immune-enhancing nutrients and to summarize current recommendations concerning the use of these nutrients.

Immune Status in Critical Illness & Injury

Patients in the intensive care unit are not, by any means, a homogenous population. Similarly, although often grouped together as “critically-ill,” their disease processes are associated with very different alterations in immune function. Innate and acquired immune responses play important roles in the body’s response to acute severe illness and injury. Local inflammation is amplified via proinflammatory mediators such as IL-1, TNF-α, and prostaglandins. When the local response becomes more widespread, the patient may exhibit the systemic inflammatory response syndrome (SIRS). In its early stages, this response is thought to be adaptive, since it may facilitate resolution of the inciting process or event. However, it is clear that an exaggerated or prolonged SIRS response is detrimental. A number of factors may contribute to this, including certain bacterial infections, a genetic predisposition to inflammation, patient age, and comorbidities. Excessive SIRS often results in syndromes such as the acute respiratory distress syndrome (ARDS), septic shock, disseminated intravascular coagulation (DIC), and multisystem organ dysfunction syndrome (MODS). One important mechanism for organ damage appears to be the overproduction of nitric oxide, which has been thought to lead to extensive mitochondrial damage.² But a number of cytokines contribute to SIRS, and the syndrome has been referred to as a “cytokine storm,” using a term that was first coined to describe the massive inflammatory response seen in severe cases of influenza.⁹

The adaptive or acquired immune response occurs several days after the inciting event and involves interaction between antigen-presenting cells (APC) and lymphocytes. These, in turn, are responsible for cell-mediated immunity and production of antibodies. Interestingly, some critically-ill patients appear to develop a transient down-regulation of adaptive immune function known as the compensatory anti-inflammatory response syndrome (CARS). This involves lymphocyte dysfunction and apoptosis, macrophage and monocyte deactivation, and increased production of interleukin-10. It may have evolved in order to prevent distant organ damage which may occur as a result of the pro-inflammatory state. In certain patients, including trauma victims, CARS can be exaggerated, resulting in a type of “immunoparalysis” with subsequently increased risk of nosocomial infections, organ dysfunction, and death.²

Immune Enhancing Nutrients

Many of the numerous enteral feeding formulas available on the market today are enriched with specialty nutrients. These include arginine, glutamine, nucleotides, both omega-3 and omega-9 polyunsaturated fatty acids, and other amino acids such as citrulline and the branched chain amino acids leucine, isoleucine, and valine (See Table 1). In Europe, alanine-glutamine dipeptide is widely used. The dipeptide is cleaved in the bloodstream to produce glutamine. In this review, we present a brief overview of these specific ingredients and their proposed role in critical illness.

Table I.

Composition of Several Immune-Enhancing Enteral Formulas

	Crucial	Peptamen AF	Impact	Vital AF 1.2	Optimental	Oxepa	Perative	Pivot 1.5
Protein (g/L)	94	75.6	56	75	51.3	62.5	66.7	94
Carbohydrate (g/L)	94	107	130	111	138.5	105.5	180.3	172
Fat (g/L)	68	54.8	28	54	28.4	93.7	37.3	50.8
Osmolality (mOsm/kg)	490	390	375	425	586	493	304	595
EPA/DHA (g/L)	2.8	2.4	1.7	2.7/1.1	3.3	6.6	0	3.9
Arginine (g/L)	15	IPS	12.5	IPS	3.6	IPS	8.0	13
Other			Nucleotides
Manufacturer	Neslé	Neslé	Neslé	Neslé	Abbott	Abbott	Abbott	Abbott

Arginine

This amino acid is commonly referred to as “conditionally essential,” meaning that, while it can be made by the body, it runs short in conditions of metabolic stress. During stress, body stores are depleted, and metabolism of arginine is increased. Especially in trauma, it is required for tissue repair. Further, the enzyme arginase is upregulated in trauma and other conditions of stress. Arginine is the precursor for urea in the urea cycle, so that conditions of increased protein breakdown may lead to increased need. Also, arginine is a precursor for proline, a key structural component of collagen, as well as for polyamines, which play important roles in regulation of cell of cellular proliferation.¹

Arginine may have very different effects in different patient populations, especially in critical illness. For example, it has been labeled deleterious in the setting of sepsis, because it is also the substrate for the several different varieties of nitric acid synthase, and it may contribute to excessive nitric oxide production. But in trauma or following major surgery, there is a relative deficit of arginine because of arginase over-expression by granulocytes. The arginine-deficient state may contribute to the CARS immunosuppressive response by decreasing translation of certain peptides on the T-cell receptor complex.²

Glutamine and the Alanine-Glutamine Dipeptide

Glutamine is the most abundant free amino acid in the body, with the majority of stores being found in skeletal muscle. Although glutamine and alanine comprise only about 6–8% of structural muscle proteins, they represent approximately 70% of amino acids released by skeletal muscle during stress and sepsis. Under these conditions, stores are rapidly depleted and glutamine too becomes an essential amino acid.¹ Glutamine provides fuel for rapidly dividing cells and, thus, has several important immune-related functions. It provides fuel for rapidly growing enterocytes, helping to maintain gut barrier function. It provides energy for leukocytes and neutrophils themselves and stimulates nucleotide synthesis. Furthermore, it acts as a precursor for glutathione, an important biologic antioxidant, and induces the production of heat shock proteins.²

Novak et al. recently published a meta-analysis of fourteen randomized trials looking at glutamine supplementation in surgical and critically-ill patients. They concluded that, in surgical patients, glutamine supplementation significantly reduced the number of infectious complications as well as length of hospital stay and overall mortality. In the critically-ill population, number of complications and overall mortality were also significantly reduced. These positive effects were most pronounced with high doses of L-alanyl-L-glutamine dipeptide.³ Unfortunately, this formulation is not available in the United States and, thus, enteral glutamine powder is most commonly used. Glutamine equivalents have also been used with reportedly good results, although their bioavailability in critical illness is not well defined.²

Omega-3 Polyunsaturated Fatty Acids

Fish oils have become widely utilized in recent years for their anti-inflammatory properties. Their active components, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be classified as omega-3 polyunsaturated fatty acids. Omega-3 fatty acids exert their anti-inflammatory effect, in part, by replacing plant-derived omega-6 fatty acids (eg. Arachadonic acid) within cell membranes. Compared to their omega-6 counterparts, when acted on by phospholipases in times of metabolic stress, omega-3 fatty acids produce metabolites, namely prostaglandin E2 and leukotriene B4, which are less inflammatory and less immunosuppressive.¹ Additionally, in experimental models, omega-3 fatty acids have been shown to downregulate production of pro-inflammatory TNF-α through inactivation of signal transduction pathways. Additional mechanisms have also been suggested. For example, studies have shown that pre-treatment with omega-3 fatty acids may decrease nitric oxide production, offering another explanation for the observed reduction in inflammation-related tissue damage that is seen with omega-3 supplementation. However, most studies have included additional supplements and, thus, it is often difficult to clearly assign them benefit.⁴

Nucleotides (RNA)

Nucleotides are low-molecular weight intracellular compounds that serve as the building blocks for DNA, RNA, and ATP. They play an active role in cell proliferation as well as immune modulation. During times of stress, rapidly dividing cells, including lymphocytes and enterocytes, rely heavily on the salvage pathway of nucleotide production, which is limited by the availability of free nitrogenous bases. Studies have demonstrated that parenteral nucleotide supplementation results in enhanced immune responsiveness as evidenced by increased lymphocyte blastogenesis. Additionally, nucleotides are thought to help maintain the integrity of the mucosal barrier within the gut. Nucleotide supplementation has been shown to mitigate the effects of endotoxin-induced mucosal damage, and is associated with decreased bacterial translocation in lipopolysaccharide-induced sepsis models.⁴

Clinical Applications

In their 2001 meta-analysis, Heyland et al. reviewed data from twenty-two randomized trials comparing immunonutrition to standard enteral formulas in critically-ill patients, trauma victims, and patients undergoing elective surgery. (See Figures 1, 2 & 3). They reported fewer infectious complications in patients receiving immunonutrition. These patients were also found to have a shorter length of hospital stay, approximately 3.3 days on average. However, this review demonstrated no overall advantage with respect to mortality in patients who received immunonutrition.⁵

Figure 1. Immunonutrition Bottle Hanging on a Patient.

Figure 2. Enteral Nutrition Administration Set.

These are designed to be unable to connect to intravenous lines. Nonetheless, errors have been made, and further standardization of enteral administration sets is ongoing.

Figure 3. Administration Pump, Designed for Enteral Nutrition.

An important safety factor is keeping the enteral nutrition administration completely separate from intravenous nutrition administration.

Arginine appeared, in their analyses, to be the critical component. In sub-group analysis, patients receiving high-arginine content formulas had fewer infectious complications, shorter hospital stay, and no difference in mortality compared to those receiving standard enteral formulas. On the other hand, patients receiving other forms of immune-enhancing nutrition were found to have no difference in number of infectious complications, longer hospital stay, and higher overall mortality when compared standard enteral nutrition.⁵

Comparing surgical patients with other critically-ill patients, no difference was found in effect of immunonutrition on overall mortality. The benefit of reduced infectious complications was only seen in the subgroup of elective surgical patients. Shorter length of hospital stay was observed in both populations.⁵

Marik and Zaloga recently conducted a separate meta-analysis of twenty-one studies including over 1900 high-risk surgical patients. They found that patients receiving immunonutrition experienced fewer infections, fewer wound complications, and shorter overall length of stay when compared to patients receiving a control enteral diet. Mortality was equal in both groups at 1%. Interestingly, these authors found that both arginine and fish oil were required in order for these benefits to be seen. Treatment effects were similar regardless of the time at which the specialized diet was initiated.⁶

One of the difficulties in studying the effects of various specialized diets lies in the inability to definitively assign effects to specific ingredients. There are several commercially available products on the market today. Table 1 below lists some of these formulas.² There are several product variants available, as well. Impact Glutamine, for example, contains glutamine 15 g/L in addition to high arginine content, 16.3 g/L.⁸

Gulidelines & Recommendations

In their 2009 Guidelines for Nutrition Support Therapy the American Society for Parenteral and Enteral Nutrition (ASPEN) outlined recommendations. “Immune-modulating enteral formulations (supplemented with agents such as arginine, glutamine, nucleic acid, omega-3 fatty acids, and antioxidants) should be used for the appropriate patient population (major elective surgery, trauma, burns, head and neck cancer, and critically-ill patients on mechanical ventilation), with caution in patients with severe sepsis.” These guidelines support use of immunonutrition in mild to moderate sepsis, while recommending against such diets in severe sepsis. These recommendations are classified as Grade A for surgical ICU patients and Grade B for medical ICU patients, recognizing that the beneficial effects are more uniformly seen in patients undergoing major surgery than in critically-ill mechanically ventilated patients.⁷

Conclusion

The most critical question regarding immunonutrition is, does it work? The answer appears to depend on more factors than have been adequately studied. The answer to the question is, “probably.” Nonetheless, there is increasing evidence that the results of postoperative patients and medical critically-ill patients can be improved by using these formulas. Clinicians should look for formulas containing arginine, glutamine, and omega-3 fatty acids (fish oil) in particular. Since these products cost more than more standard forms of enteral nutrition, they should not be used indiscriminately. Finally, the use of these nutrients in parenteral nutrition, while relatively common in Europe, is not yet standard practice in North America.

Biography

Graham R. Y. Pollock, MD, is a Resident in the Department of Surgery at University of Missouri – Kansas City School of Medicine Charles W. Van Way, III, MD, FACS, FCCP, FCCM, MSMA member since 1989, (above) is Professor of Surgery, the Sosland/Missouri Endowed Chair of Trauma Services, and the Director of the Shock Trauma Research Center at the University of Missouri – Kansas City School of Medicine.

Contact: pollockg@umkc.edu