How Can Pharmaconutrition Benefit Patients in the ICU?

NASHVILLE—Nutritional substrates can be used for critically ill patients not merely as supportive care, but as therapy that targets the underlying disease process and impacts specific patient outcomes, according to several investigators who spoke at the Society of Critical Care Medicine 2009 Critical Care Congress. Supplements, such as zinc, arginine, and glutamine, are being studied to answer questions about timeliness of administration, amount of therapy needed, and which patients should receive which combination of nutrients.

NUTRITION AS THERAPY

Daren K. Heyland, MD, Director of Research at the Critical Care Program at Kingston General Hospital in Ontario, explained how thinking of nutrition in terms of supportive care is giving way to a new paradigm—one in which nutrition is used to modulate the inflammatory cascade caused by critical illness. In this model, nutrition research is focused on investigating ways supplementation can “minimize the inflammatory response, support the mitochondria, attenuate oxidative stress, and at the same time preserve native immunity,” he said.

The use of fish oils, for instance, is what Dr. Heyland described as “a prototypic example of pharmaconutrition strategy.” He noted that the dietary content of fish oils impacts the composition of inflammatory cell membranes, which in turn influences immunity and the inflammatory condition of the patient by way of gene expression, cytokine production, membrane structure and fluidity, and other factors. A meta-analysis of five randomized controlled trials of fish oil–supplemented enteral diets in critically ill patients showed that they were associated with a reduction in mortality, he stated.

“The composition of inflammatory cells does in fact change and lead to increased levels of eicosapentanoic acid and docosohexanoic acid, which ultimately impacts expression of tumor necrosis factor-alpha, leading to significantly reduced interleukin (IL)-6 and other inflammatory cytokines,” he said.

However, Dr. Heyland highlighted the need for large, properly designed multicenter studies in order to confirm this and other findings. For example, future trials should take into account data that shows the treatment effect may be modified by pre-ICU nutritional risk, where low BMI and high BMI patients receive the most benefit. Nevertheless, he stated that the future of nutritional trials is promising: Two decades ago, the average sample size for nutrition studies was 50, compared to an average of 100 today—a number that is continuing to trend higher. In addition, the number of randomized controlled trials and multicenter trials in nutrition research is increasing.

“If you want to think about nutrition as therapy, we want to be more discriminate about the patient populations that we’re trying to apply these results to,” he said. “We need to discourage studies designed in heterogeneous cohorts, because it is likely that these nutritional strategies will make the most difference in the sickest patients with a homogeneous illness.”

ZINC SUPPLEMENTATION

Among the pharmaconutrition options for the ICU currently under investigation is zinc supplementation, which is being studied due to its variety of effects on organ systems and body functions affected by critical illness. Natalie Z. Cvijanovich, MD, Associate Physician at Children’s Hospital and Research Center, Oakland, California, explained that zinc is essential for the function of the innate and adaptive immune system as it is involved in gluconeogenesis, synthesis of acute phase proteins, endocrine pancreatic function, and normal growth and wound healing.

“There have been many zinc clinical trials, but mostly in the setting of developing countries, where preexisting nutritional zinc deficiency is quite common,” Dr. Cvijanovich remarked.

In an American observational study published in 2009 involving 20 critically ill children with at least one organ failure or a Pediatric Risk of Mortality III score of 5 or higher, Dr. Cvijanovich and colleagues found that all patients had low plasma zinc levels upon admission to the pediatric ICU. Furthermore, the lower the zinc levels were, the greater the degree of organ failure.

They also found an inverse relationship between zinc levels and the inflammatory markers C-reactive protein and interleukin-6. While the study provided a basis for larger studies to determine which patients may benefit from zinc supplementation, several key questions remain unanswered in the literature—such as whether supplemental zinc may actually be pro-inflammatory.

"Is the goal to replete zinc and bring back normal levels, or is there danger in supplementing to super-physiologic levels?” Dr. Cvijanovich said. “There is some research suggesting that low zinc levels may be protective. Does zinc augment bacterial adherence in vivo? It does in vitro, according to the results of some older studies.”

Appropriate dosing strategies that achieve desired beneficial effects without potential adverse effects also are not known currently. As only four randomized trials have examined the effect of zinc on clinical outcomes in critically ill patients, the evidence to recommend routine high-dose zinc supplementation in the ICU is insufficient, concluded Heyland et al in a 2008 paper.

“Manipulating zinc may be a new pharmaconutritional avenue,” Dr. Cvijanovich stated. “There is some evidence it would be beneficial in the field of traumatic brain injury, and almost certainly in patients with burns—in which case the clinician might not be supplementing, but actually restoring. Although we still don’t know how best to administer it, probably parenterally would be the way to go.”

ARGININE AND SURGERY

Meanwhile, arginine is a nutritional supplement that has demonstrated benefits in patients requiring surgery, as it has been shown to decrease the rate of infection and length of stay by aiding T-cell function and replenishing depleted arginine stores.

Lindsay Weitzel, PhD, of the Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, explained that arginine levels in plasma are significantly lower following surgery or trauma than in a control population. After an injury or surgery, there is alternative macrophage activity, arginine deficiency, and a T-helper 2 cytokine profile. This is in contrast to sepsis patients, who have classic macrophage activity, nitric oxide, no arginine deficiency, and a T-helper 1 cytokine profile.

“This is the paradox of arginine administration: After elective surgery or trauma, there is a significant decrease in infections with the administration of arginine, but after diagnosis with sepsis, there could be an indication of worse outcomes,” Dr. Weitzel said.

Dr. Weitzel reported a new meta-analysis consisting of 28 randomized controlled trials from 1999 to 2008 and involving more than 3,000 surgical patients. In the arginine-supplemented diet group, there was a decrease in overall infectious complications (relative risk [RR], 0.60). A subgroup analysis also showed an RR of 0.60 for gastrointestinal (GI) surgery patients, compared to an RR of 0.52 in non-GI surgery patients. Among patients who were treated with arginine both preoperatively and postoperatively, there was an absolute risk reduction in infectious complications of 49%, compared to 37% among patients treated only postoperatively. Length of stay was shorter among surgical patients treated with arginine, and no evidence of harm was reported in treated patients.

“Arginine deficiency is real and has negative biological consequences, including immune suppression, abnormal microperfusion, and abnormal wound healing,” Dr. Weitzel emphasized. “Perioperative administration of arginine-containing immune-modulating nutrition should be a standard of care for major GI and cardiac surgery patients to reduce postoperative infection.”

CONVINCING EVIDENCE IN GLUTAMINE RESEARCH

Glutamine, a nonessential amino acid and the most abundant free amino acid in the body, has been much studied as a candidate for nutritional supplementation for critically ill patients, explained Richard D. Griffiths, MD, Professor of Medicine in the School of Clinical Sciences at the University of Liverpool, United Kingdom. In his presentation, Dr. Griffiths conveyed that a well-evidenced conditional deficiency of glutamine exists in humans during critical illness and that the continued omission of glutamine in parenteral nutrition is no longer justified on the basis of extensive clinical outcome studies. He asserted that there is more outcome evidence for this one nutrient than is available for any other nutrient and most treatments within intensive care.

In a study led by Dr. Griffiths in 84 ICU patients unable to tolerate enteral feeding, parenteral glutamine supplementation was found to reduce mortality rates and also the incidence of Candida infections. A meta-analysis of four level 1 studies and 10 level 2 studies using parenteral glutamine showed a reduced mortality risk (RR, 0.71).

Dr. Griffiths acknowledged limitations in glutamine trials common to many nutrition studies, including small sample size with only a few patients showing a testable benefit, unclear results as to timing of administration, and studies not performed under tight glycemic control. Nevertheless, “the evidence in favor of glutamine use is robust—more so than for any other amino acid,” he added. “Patients on glutamine have a huge dose tolerance. The survival outcome evidence is impressive.

“We can wait for the results of other studies if we want to,” Dr. Griffiths said, such as the ongoing REDOXS (Reducing Deaths Due to Oxidative Stress) Study, a randomized trial of parenteral glutamine and antioxidant supplementation, “but using glutamine is a safe thing to do.”

ESSENTIAL TRACE ELEMENTS

While published studies have demonstrated evidence of clinical benefits associated with glutamine, zinc, and selenium monotherapy, how should essential trace elements be administered in relation to each other? Mette M. Berger, MD, PhD, of the Department of Intensive Care Medicine and Burns Center at Lausanne University Hospital in Lausanne, Switzerland, suggested that clinicians should consider giving nutritional therapies in combination, rather than alone, as the former treatment modality has a better safety profile.

“Trace-element deficiency is a killer, or at the very least delays recovery. Substitution of specific losses is essential to restore antioxidant and immunity capacity,” Dr. Berger said.

“The sickest patients should have a combination of micronutrients, as losses usually do not involve a single trace element.” By the same token, supplementing patients with very large doses of a single micronutrient in absence of losses may not be beneficial, as this may lead to toxicity, she explained.

In a 2007 randomized, placebo-controlled trial conducted by Dr. Berger and colleagues, 21 patients with major burns were administered intravenous doses of copper, selenium, and zinc combination treatment. Trace-element substitution was associated with improved clinical outcomes, including fewer pulmonary infections and better wound healing, compared with placebo. It was also associated with higher circulating plasma and skin tissue contents of selenium and zinc, and improved antioxidant status. The agglomeration of two burn trials showed a highly significant reduction of nosocomial pneumonia.

In a 2008 trial, Dr. Berger and colleagues examined the role of early micronutrient administration in 200 critically ill cardiac surgery and trauma patients with oxidative stress. While the intervention (ie, selenium, zinc, vitamin C and vitamin B1) did not reduce early organ dysfunction, it did cause a significant reduction in the inflammatory response, and length of hospital stay in trauma patients. Although infectious complications did not differ between patients who received supplementation and those on placebo, plasma concentrations of selenium, zinc, and glutathione peroxidase increased to within normal values in the treatment group.

—John Merriman

Suggested Reading
Berger MM, Baines M, Raffoul W, et al. Trace element supplementation after major burns modulates antioxidant status and clinical course by way of increased tissue trace element concentrations. Am J Clin Nutr. 2007;85(5):1293-1300.
Berger MM, Soguel L, Shenkin A, et al. Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients. Crit Care. 2008;12(4):R101.
Cvijanovich NZ, King JC, Flori HR, et al. Zinc homeostasis in pediatric critical illness. Pediatr Crit Care Med. 2009;10(1):29-34.
Heyland DK, Jones N, Cvijanovich NZ, Wong H. Zinc supplementation in critically ill patients: a key pharmaconutrient? JPEN J Parenter Enteral Nutr. 2008;32(5):509-519.
Kalil AC, Sevransky JE, Myers DE, et al. Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock. Crit Care Med. 2006;34(11):2719-2728.
McQuiggan M, Kozar R, Sailors RM, et al. Enteral glutamine during active shock resuscitation is safe and enhances tolerance of enteral feeding. JPEN J Parenter Enteral Nutr. 2008;32(1):28-35.

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