Immunomodulating Nutrients Not Helpful in Enteral Feeding

Norra MacReady

August 06, 2014

Immunomodulating nutrients added to enteral feedings given to mechanically ventilated patients in the intensive care unit (ICU) do not decrease the incidence of infection, a new study suggests. They may in fact be associated with a greater mortality risk than standard, high-protein enteral nutrition.

"We believe that these observations should lead to a critical appraisal of current guidelines on the use of immune-modulating nutrients in mechanically ventilated critically ill patients," Arthur R.H. van Zanten, MD, PhD, and colleagues write in an article published in the August 6 issue of JAMA.

In several meta-analyses, adding immunomodulating nutrients such as glutamine, arginine, nucleic acids, omega-3 fatty acids, selenium, and antioxidants to enteral feeding formulas has been associated with reduced infectious disease and improved recovery compared with standard enteral nutrition, the authors write. However, the European Society for Clinical Nutrition and Metabolism has concluded there is no general indication for administering immune-modulating nutrients to critically ill patients, whereas the Society of Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition both support the use of these nutrients in appropriately selected patients.

In their study, called the MetaPlus Trial, Dr. van Zanten, from the Department of Intensive Care, Gelderse Vallei Hospital, Ede, the Netherlands, and colleagues compared administration of a standard high-protein enteral nutritional formula (HP) with a similar formula enriched with immunomodulating nutrients (IMHP) in critically ill patients receiving mechanical ventilation.

The MetaPlus Trial was a randomized, double-blind, parallel-group study performed in 14 ICUs across the Netherlands, France, Germany, and Belgium. Patients were enrolled from February 23, 2010, through November 14, 2011. They were all 18 years old or older and assigned on a 1:1 basis to receive either the standard HP enteral formula or an IMHP preparation enriched with glutamine, omega-3 fatty acids, and antioxidants. The 2 products were identical in appearance, smell, and texture, as well as in calorie and nitrogen content. The patients were fed according to routine practice, with a target energy requirement of 25 kcal/kg of body weight per day and a total maximum energy intake of 2500 kcal per day.

The authors recorded the patients' age, sex, height, weight, medical history, smoking behavior, alcohol consumption, preexisting conditions, use of medications, and administration of chemotherapy or radiotherapy during the previous 3 months. They also calculated each patient's sequential organ failure assessment score, which predicts ICU mortality based on clinical data and laboratory results. In addition, the researchers determined each patient's acute physiology and chronic health evaluation II (APACHE II) score, another predictor of hospital mortality, at baseline. The primary end point of the study was the incidence of new infections from the start of study product administration until ICU discharge or for a maximum of 28 ICU days.

The primary analysis included 152 patients in the IMHP group and 149 in the HP group. At baseline, the groups had a mean age of 57 years (standard deviation [SD], 19 years) and 59 years (SD, 18 years), respectively. The IMHP group consisted of 100 men (66%) and 52 women (34%), and there were 102 men (68%) and 47 women (32%) in the HP group. The mean APACHE II scores in the IMHP and HP groups were 22.0 (SD, 8.5) and 21.3 (SD, 7.7), respectively, with an adjusted predicted mortality of 39.8% (SD, 27.3%) and 37.4% (SD, 12.9%), respectively. None of these differences were statistically significant. In both groups, trauma was the most common admission diagnosis. Other common diagnoses in both groups were sepsis, neurologic disease, and pulmonary disease.

The incidence of new infections did not differ significantly between the groups. New infections occurred in 80 patients (53%; 95% confidence interval [CI], 44 - 61) in the IMHP group and 78 patients (52%; 95% CI, 44 - 61; P = .96) in the HP group. Similarly, there were no significant differences in the total number of infections in each group, number of infections per patient (P = .73), number of infections per ICU day per patient (P = .97), or duration of each patient's infections (P = .71). There were also no differences in the incidence of infections at any particular site, such as the urinary tract (P > .99), surgical site (P = .33), or pneumonia (P = .64).

There was, however, a difference in 6-month mortality: in a Cox proportional hazard regression analysis, administration of IMHP was associated with a hazard ratio for mortality of 1.57 (95% CI, 1.03 - 2.39; P = .04). The analysis was adjusted for age, sex, body mass index, APACHE II score, adjusted predicted mortality, baseline sequential organ failure assessment score, baseline glutamine, glucose, type of patient (medical, surgical nontrauma, surgical trauma, trauma nonsurgical), time between starting the study product and ICU admission, occurrence of preexisting infections, and antibiotic treatment at study initiation.

These findings "contrast published meta-analyses stating that immune-modulating enteral nutrition was associated with reductions in infectious morbidity and improved recovery in critically ill patients compared with standard high-protein enteral nutrition," the authors write. However, they cite other studies in which the addition of glutamine to enteral nutrition was associated with either no change or an increase in infectious complications or mortality among patients in the ICU. Disappointing findings also have been reported in recent studies involving the addition of omega-3 fatty acids and other lipids to enteral feedings. The MetaPlus Trial involved lower doses of the immunomodulating nutrients than in these other trials but produced similar results, suggesting that "harmful effects may also be present using these lower dosages," the authors write.

There are most likely multiple reasons why the enriched formulas have proven ineffective, Todd W. Rice, MD, writes in an accompanying editorial. Timing may be one. "Waiting until a patient is critically ill may be too late to meaningfully alter the course of the inflammatory cascade, which has already progressed to the point of causing the patient to become critically ill." It is also possible that these "immunomodulatory" nutrients do not alter immune function at all. Or perhaps they do their job too well, writes Dr. Rice, from the Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. " 'Modulating' a highly inflammatory immune system may offset any beneficial effect that a robust immune response has in the fight to recover from multisystem organ failure."

It is possible that some specific critically ill populations may benefit from the addition of certain nutrients to their enteral feedings, Dr. Rice concludes. However, although these and other questions remain to be answered, "the similarity of the results and the suggestion of harm from recently published, large, randomized trials of immunonutrition should strongly discourage intensivists from its routine prescription for critically ill patients in clinical practice outside the scope of well-designed randomized clinical trials."

The study was sponsored by Nutricia Advanced Medical Nutrition, Nutricia Research, Utrecht, the Netherlands. Dr. van Zanten and several coauthors have reported that they received honoraria for advisory board meetings, lectures, and travel expenses from Abbott, Baxter, Danone, Fresenius Kabi, Nestle, Novartis, and Nutricia. Other coauthors have received honoraria and other types of funding from Sanofi, Takeda, BBraun, Bayer Healthcare, CSL Behring, L.ser medizintechnik, Astellas Pharma, MSD, Merck, Pfizer, and 3M. Inclusion fees for patients in the MetaPlus trial from Nutricia were paid to the local ICU research foundations or to participating hospitals. Dr. Rice has disclosed no relevant financial relationships.

JAMA. 2014;312:490-491, 514-524. Abstract

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