Pharmaconutrition: A New Emerging Paradigm
Daren K. Heyland, MD
Kingston General Hospital
Kingston, Ontario, Canada
The results of the largest randomized trial of an immune-enhancing diet were published recently in Intensive Care Medicine. In a multicenter, randomized, double-blind, controlled trial, Kieft et al compared an enteral formula enriched with arginine, glutamine, antioxidants and omega-3 fatty acids to an isocaloric, non-isonitrogenous standard enteral formula in a mixed population of 597 critically ill patients. (1) When examined using an efficacy analysis (those fed for more than 48 hours) and by an intention to treat analysis, the authors failed to demonstrate any difference in clinical outcomes in the overall analysis or several subgroup analyses. Mortality rates, infectious complications, intensive care unit (ICU) length of stay and duration of mechanical ventilation were the same in the two groups.
When the results of this large trial are added to those of existing trials in the form of a meta-analysis, the overall treatment effect is consistent, with no effect on mortality rates (relative risk [RR], 1.05; 95% confidence intervals [CI], 0.90, 1.25) or infectious complications (RR, 0.97; CI, 0.81, 1.15). (2) After 20 years of research, more than 20 randomized trials of 2,348 critically ill patients and millions of research dollars, why are we unable to demonstrate a positive treatment effect associated with these immune-enhancing products? Do we need more trials like this one to prove the virtues of these special nutrients? Or, do we have to ask ourselves whether there are fundamental problems with our approach to proving the hypothesis that certain nutrients with immunologic and metabolic properties will improve the outcomes of critically ill and injured patients? Perhaps the problem relates to the fact that multiple nutrients are combined into single nutritional products and tested in heterogeneous patient populations.
For any sick patient, “metabolic resuscitation” of the gastrointestinal tract using adequate nutrition in general, and defined immunomodulating substrates specifically, to maintain gut barrier integrity and function and to reduce regional oxidative stress, will have to be considered a key therapeutic strategy. However, within a given patient over time or across different patient populations, the severity of “gut failure,” the amount of bacterial translocation, the degree of cellular immune dysfunction, the balance of inflammation/anti-inflammation, and the regional and systemic generation of reactive oxygen species (ROS) will vary. Generally speaking, elective surgical patients experience minimal activation of cytokines and some degree of suppression of the cellular defense function following surgical stress, putting them at higher risk for acquired infectious morbidity and mortality. Therefore, nutrients such as arginine that stimulate the cellular defense system may reduce infectious complications in the elective surgical patient. In contrast, the associated changes to the systemic inflammatory response accompanying critical illness are far more intense, complex, and variable and less well-defined. They are best characterized by an overamplified inflammatory response, probably due to excess nitric oxide, ROS, and excessive availability of lipid mediators. Thus, nutrients such as arginine that further stimulate the systemic inflammatory response may be deleterious in critically ill and injured patients. In fact, novel therapies that have been shown to be effective in the early phase of critical illness decrease the inflammatory response associated with critical illness; they do not stimulate it. (3,4)
The notion that hyperinflammation and cellular immune dysfunction coexist in the same patient or patient population at the same time is emerging in the literature. (5) This means that, for critically ill patients, nutrients that augment cellular defense (specific and nonspecific immune function) and ameliorate ROS without a collateral increase in the inflammatory response are most likely to be beneficial. The treatment effect of various substrates or nutrients will vary depending on the underlying pathophysiology of the host and whether the substrate influences cellular immune function, the synthesis of inflammatory mediators, and/or the generation of ROS. To combine these nutrients with immune-enhancing effects into single products delivered to heterogeneous groups of patients seems fundamentally flawed. It is plausible that some of these nutrients, tested individually, may have some positive (or negative) therapeutic benefits in some groups of patients. However, when combined and exposed to heterogeneous groups, as best illustrated by the study by Kieft et al, (1) any indication of benefit (or harm) is lost.
When the Canadian Clinical Practice guidelines for nutrition support in the mechanically ventilated patient were developed, an attempt was made to isolate the effect of individual nutrients in specific homogenous critically ill patient populations. This was difficult, as there are no studies testing the effect of arginine alone in critically ill patients. (6) The team had to infer what the effect of arginine might be in these patients using products that contained supplemental arginine and other supplemented nutrients. Based on reviews of the literature, glutamine and antioxidant strategies are most likely to be beneficial to critically ill patients. (7,8) What is most interesting in the studies included in these reviews is that they tested the beneficial effect of a single nutrient (such as glutamine or selenium) in a patient receiving balanced nutrition. In such a study, one is able to see the signal that the nutrients are responsible for an apparent mortality reduction, independent of the nutrition provided. This suggests that the way forward is to test single nutrients in large-scale, well-designed, randomized trials of homogenous patient populations.
Before doing so, the medical community must understand the optimal dose and method of delivery of such nutrients. Dose-finding studies are very rare in the nutrition literature. One reason why some randomized trials have failed to demonstrate a treatment effect may be related to inadequate dosing. The results of the glutamine and antioxidant meta-analyses (8,9) seem to suggest that a higher dose of glutamine and selenium is associated with a greater treatment effect. When the study nutrients are provided enterally and combined with the enteral nutrition product, given that these sick patients may have trouble tolerating their enteral feeding, reduction in the intake of feeding limits the intake of these key nutrients. Future studies should dissociate the study nutrients from the intended nutrition so that if there are issues with tolerance of standard nutrition support, the delivery of the study nutrients is not compromised. This is a unique concept that represents a major advance in the design of studies in this area.
In conclusion, the current approach to defining those key nutrients that may have positive effects in critically ill patients is not working. We need a new scientific paradigm to illuminate future prospects. This paradigm includes focusing on single nutrients dissociated from nutrition tested in homogenous patient populations in large, rigorously designed randomized clinical trials. Perhaps the label immunonutrition represents the “old” approach. Can the term pharmaconutrition represent the new paradigm?
