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Nutritional Modulation of Immunity and Metabolism
Robert G. Martindale, MD, PhD
Oregon Health and Science University
Department of Surgery
Portland, Oregon
Laszlo Kiraly, MD
Oregon Health and Science University
Department of Surgery
Portland, Oregon
The objectives of nutritional support in critically ill populations have evolved from prevention of
malnutrition to therapeutic modulation of vital organ function and support of key processes such
as immunity, inflammation and antioxidant defenses. Nutrients traditionally have been viewed as
a means to provide basic energy for cellular homeostasis and amino acids for protein synthesis;
however, critically ill, surgical and trauma patients are in a constant dynamic state between
systemic inflammatory response (SIRS) and compensatory anti-inflammatory response (CARS).
Compelling evidence now supports the concept that specific nutrients can modulate the immune
and/or metabolic response in critically ill patients (Figure 1). [1] Nutrients such as fish oils,
arginine, glutamine, leucine, antioxidants, nucleic acids and other pharmaconutrients, given at
levels higher than those needed for “normal” metabolism, are becoming an accepted as part of
intensive care unit (ICU) therapy. The recent nutrition support guidelines for critical care,
developed in a collaboration between the Society of Critical Care Medicine and the American
Society for Parenteral and Enteral Nutrition, describe the rationale for the use of such formulas.
The use of immune and metabolically active agents in the ICU received a grade A
recommendation, supported by 15 level-2 studies and six level-1 studies. [2]
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The physiologist John Hunter, in 1784 in his book, “A Treatise on Blood, Inflammation and
Gunshot Wounds: A Mechanism of Inflammation and a Comment That,” noted “many types of
injury produce a similar inflammation.” Sir William Osler, in 1904, was quoted as saying
“except on few occasions the patient appears to die from the body’s response to infection rather
than from it.” These two insightful comments describe a major focus of critical care and trauma
in 2010. Attempting to attenuate or control the metabolic response to stress and trauma at a
manageable level, rather than allowing the extremes of the SIRS and the lows associated with
CARS, is now a key to optimal ICU care. The physiologic response to stress is well described
and includes a hyperdynamic cardiac and pulmonary response, insulin resistance, hyperglycemia,
accelerated protein catabolism from the muscle, poor adaptation to use of alternate fuels, and
increased oxidative stress. If the catabolic response goes on unabated, complex immunological
changes result in immune suppression. [3] These observations in the critically ill population
clearly indicate that delivery of just “calories and protein” to the persistently hyperdynamic
stressed patient is not adequate. The concept of using specific nutrients for metabolic control was
proposed in the late 1980s and now has become the standard of care for many critically ill,
traumatized and surgical patients.
The use of the omega-3 fatty acids (primarily eicosapentaenoic acid [EPA] and docosahexaenoic
acid [DHA]) is at the center of this “pharmaconutrition” evolution. The ability to use specific
nutrients to attenuate the metabolic response, reverse or minimize the loss of lean body tissue,
prevent oxidative injury and favorably modulate the immune and inflammatory response is now
available. These benefits have been noted by the appropriate use of omega-3 fatty acids, usually
in the form of fish oil, arginine, glutamine and select other nutrients as part of enteral and
parenteral nutrition programs. [2]
Traditionally, lipids were felt to be important in clinical nutrition, but only as a source of calories
and essential fatty acids and as support for the absorption of fat-soluble vitamins via micelle
formation. Recent translational research has shown that fish oils can alter metabolic response to
stress through multiple mechanisms; these include changes in membrane phospholipids yielding
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a less inflammatory profile of leukotrienes, thromboxanes and prostaglandins; alterations in gene
expression; and modulation of endothelial expression of intercellular adhesion molecule 1
(ICAM-1), E-selectin and other endothelial receptors regulating vascular integrity and function.
[4] Additionally, EPA and DHA derivatives produced endogenously, including resolvins,
docosatrienes and neuroprotectins, are potent active effectors of inflammation resolution. [5,6]
Resolvins regulate polymorphonuclear neutrophil transmigration. Docosanoids and
neuroprotectins are both derived from DHA and have potent neuroprotective properties.
Neuroprotectin decreases neutrophil infiltration, proinflammatory gene signaling and NFκB
binding. Neuroprotectin D1 has been found to reduce neural infarct volume by half in an animal
ischemia-reperfusion model. [7,8] These protective mediators are highly conserved among
species, from fish to mammals. [5] With the discovery of these compounds, inflammation
resolution is acknowledged as an active process rather than a passive time-dependent one. In
addition to the mechanisms mentioned, it has become apparent that fish oils also have a
regulatory influence on the vagus nerve, as they have recently been shown to dampen the
inflammatory response mediated via the vagal fibers. [9]
The cardiac-stabilizing influence of fish oils has drawn interest in various acute clinical settings.
Long-term consumption has protective effects against cardiac disease in large population studies.
[10] Recently attention has focused on the acute effects of fish oils on the cardiac membrane. In
2005, Calo et al reported a randomized clinical trial in coronary artery bypass patients showing a
54% reduction in perioperative atrial fibrillation. [11] Several other reports have elucidated the
potential mechanisms. [9,12]
The greatest debate in the area of pharmaconutrition revolves around supplemental arginine use
in the ICU setting. One school of thought holds that arginine is potentially toxic, whereas another
argument is that arginine is deficient in critical illness and sepsis and should be supplemented.
[13] A complete explanation and support for each argument are beyond the scope of this article
and can be found in recent peer-reviewed articles. [14-16] No prospective clinical data support
the concept that arginine is harmful, whereas numerous prospective articles have demonstrated
supplemental arginine to be beneficial, especially in the surgical and trauma population. [17]
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Glutamine is the other conditionally essential amino acid that has gained support in the critical
care setting. Over the past 20 years, it has been reported to offer a myriad of benefits, including
maintenance of acid-base balance, primary fuel for rapidly proliferating cells (i.e., enterocytes
and lymphocytes), precursor in the synthesis of glutathione and arginine, reduction of insulin
resistance and key substrate for gluconeogenesis. [18]
Recent evidence that glutamine can induce heat-shock protein within several tissue beds is yet
another beneficial molecular effect of this versatile amino acid. [18] The heat-shock proteins are
a class of cellular chaperone proteins that support appropriate protein folding. By enhancing the
these proteins, the cell protects itself from subsequent stress. [19]
Numerous human studies have reported benefits from various combinations of metabolically
active nutrients, including fish oils (DHA and EPA), arginine, glutamine, nucleic acids, and antioxidants. The disease states benefiting from these metabolic modulating formulations are wide
ranging and spread over several systems. The nutrients have been shown to lower the incidence
and severity of acute lung injury and adult respiratory distress syndrome, decrease adverse
cardiac events and enhance early recovery from gastrointestinal surgery. Metabolic modulating
formulas also have been shown to attenuate some of the adverse metabolic effects of sepsis. Not
only have these human clinical studies shown benefit in shortening hospital stay and decreasing
infections, but several have reported lower mortality rates. [20-22] Although the data
overwhelmingly support the use of metabolically active agents, the optimal delivery route,
timing of delivery, and dosage in trauma and critical care settings have yet to be determined by
high-quality dose-response studies.
The concept of pharmaconutrition is now clearly accepted by most clinicians. Ongoing studies
will elaborate further which patient populations will maximally benefit. The use of fish oils,
arginine, glutamine and other metabolically active nutrients is now becoming part of trauma and
critical care nutrition protocols. Research focusing on the mitochondria and nucleus as nutrient
sites of action will bring a whole new understanding of metabolic control in the critically ill
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population. The principle of using nutrients as a therapeutic strategy rather than supportive one
requires a shift in current dogma. Whether nutrients are used in combination or individually,
these agents should be part of the intensivist’s armamentarium.
Diagram 1: Metabolic Modulation with EPA and DHA
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