557133
research-article2014
PENXXX10.1177/0148607114557133Journal of Parenteral and Enteral NutritionEvans and Hegazi
Commentary
Immunonutrition in Critically Ill Patients: Does One Size Fit All? David C. Evans, MD1; and Refaat A. Hegazi, MD, PhD, MPH2,3
Van Zanten and colleagues in the August 6, 2014, issue of the Journal of the American Medical Association (JAMA) reported the results of the MetaPlus study, a randomized double-blind multicenter trial of immune-modulating nutrition (IN) conducted in 301 adults in mixed medical, surgical, and trauma intensive care unit (ICU) populations.1 Patients were fed with a 25-kcal/kg caloric target and randomized to an experimental enteral IN formulation offering 1.28 kcal/mL, 59 g protein/L, 20 g glutamine/L, ω-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, and high doses of vitamins C and E, selenium, and zinc vs standard isocaloric, isonitrogenous, high-protein enteral nutrition (EN) with 6 g glutamine/L. The authors demonstrated a lack of benefit from IN for the primary end point—the incidence of new infections (53% in the IN group vs 52% in the standard high-protein EN group, P = .96). No benefit was noted for the other end points, including mortality, ventilator days, and ICU and hospital length of stay. Even more surprisingly, they reported increased mortality with IN in the medical ICU patient subgroup at 6-month follow-up (54% in the IN group vs 35% in the EN group, P = .04). MetaPlus adds to mounting evidence challenging the role of aspects of IN in critical illness. As the readers of the Journal of Parenteral and Enteral Nutrition are well aware, the premise of IN is modulation of dysregulated immune responses to achieve a therapeutic benefit. Multiple studies of IN have demonstrated certain improved outcomes in various patient populations, but many were affected by poor selection of control diets, inconsistently defined patient populations, and other methodologic limitations. IN is a broad category that encompasses enteral formulas designed to target disparate physiologic states via 2 distinct mechanistic processes: the first by attenuating excessive inflammatory responses in conditions such as acute respiratory distress syndrome (ARDS) and the second by supplementing conditionally essential nutrients (eg, glutamine, arginine, carnitine) that are rapidly depleted in certain stress states like trauma or surgery. Precise pharmaconutrient recommendations and levels of evidence vary based on disease state.2 The van Zanten et al1 study included mechanically ventilated patients without any characterization of the type of inflammation or dysregulated immune responses such as by measuring C-reactive protein or cytokine levels. Enteral
Journal of Parenteral and Enteral Nutrition Volume XX Number X Month 201X 1–2 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0148607114557133 jpen.sagepub.com hosted at online.sagepub.com
glutamine supplementation was a key aspect of the trial, but the recent REDOX trial demonstrates that high doses of glutamine (administered by both intravenous and enteral routes) in critically ill patients with severe sepsis are associated with lower survival.3 In addition, glutamine is a precursor to arginine, and there are theoretical grounds for concern about the use of arginine in patients with severe sepsis. In light of building doubts about the benefits of individual key “immunonutrients,” we must ask, “When is IN still indicated, and which immunonutrients contribute to improved outcomes?” The authors do not highlight it in the discussion, but in the online supplement to their JAMA article, they provide key subgroup findings as guidance: 6-month survival was reduced in medical ICU patients receiving IN, but there was no difference noted between IN and standard high-protein formula in surgical and trauma patients. This is reasonable given numerous studies suggesting the benefits of IN for surgical patients—but only in the postoperative setting when repletion of conditionally essential nutrients is crucial and not preoperatively as an immune-modulating strategy vs standard high-protein nutrition supplements.4 Collectively, recent data suggest that the immunemodulating nutrients must be individually considered based on mechanism of action, timing and method of use, dosage, and
From 1The Ohio State University, Columbus, Ohio, 2Abbott Nutrition, Research & Development, Columbus, Ohio; and 3Department of Internal Medicine, The Brody School of Medicine–East Carolina University, North Carolina. Financial disclosure: D.C.E. has received educational grants from Nestle Nutrition and Abbott Laboratories and speaking honoraria from Abbott. R.H. is an employee of Abbott Laboratories. Conflicts of interest: D.C.E. is director of nutrition support at The Ohio State University and recipient of educational grants from Abbott Laboratories and Nestle Nutrition and speaking honoraria from Abbott. R.A.H. is medical director at Abbott Nutrition and a full-time employee and shareholder of Abbott Laboratories. Their opinions are based on the literature and science and do not reflect those of their employers. Received for publication September 17, 2014; accepted for publication October 3, 2014. Corresponding Author: Refaat A. Hegazi, MD, PhD, MPH, Research & Development, Abbott Nutrition, 3300 Stelzer Rd, Columbus, OH 43219, USA. Email: [email protected]
Downloaded from pen.sagepub.com at BRIGHAM YOUNG UNIV on January 16, 2015
2
Journal of Parenteral and Enteral Nutrition XX(X)
disease setting. Future trials should focus on patient populations with clear measurable mechanistic derangements of immune function that are amenable to targeted IN strategies rather than a one-size-fits-all therapy broadly applied to all critically ill patients. Modulation of the immune response in the setting of systemic inflammatory response syndrome has been the goal of much research in sepsis, ARDS, trauma, and burn. A variety of drugs have shown promise in basic science and animal models, but in more than 100 human trials, no pharmaceutical therapy has ever emerged as a successful modulator of immune dysfunction of ICU patients.5 In this context, we must be cautious in suggesting that IN may offer the panacea for all critically ill patients. One size may not fit all.
References 1. van Zanten AH, Sztark F, Kaisers UX, et al. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. JAMA. 2014;312(5):514-524. 2. Hegazi RA, Wischmeyer PE. Clinical review: optimizing enteral nutrition for critically ill patients—a simple data-driven formula. Crit Care. 2011;15(6):234. 3. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368(16):1489-1497. 4. Hegazi RA, Hustead DS, Evans DC. Preoperative standard oral nutrition supplements vs immunonutrition: results of a systematic review and metaanalysis [published online June 27, 2014]. J Am Coll Surg. 5. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20(4):195-203.
Downloaded from pen.sagepub.com at BRIGHAM YOUNG UNIV on January 16, 2015
research-article2014
PENXXX10.1177/0148607114557133Journal of Parenteral and Enteral NutritionEvans and Hegazi
Commentary
Immunonutrition in Critically Ill Patients: Does One Size Fit All? David C. Evans, MD1; and Refaat A. Hegazi, MD, PhD, MPH2,3
Van Zanten and colleagues in the August 6, 2014, issue of the Journal of the American Medical Association (JAMA) reported the results of the MetaPlus study, a randomized double-blind multicenter trial of immune-modulating nutrition (IN) conducted in 301 adults in mixed medical, surgical, and trauma intensive care unit (ICU) populations.1 Patients were fed with a 25-kcal/kg caloric target and randomized to an experimental enteral IN formulation offering 1.28 kcal/mL, 59 g protein/L, 20 g glutamine/L, ω-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, and high doses of vitamins C and E, selenium, and zinc vs standard isocaloric, isonitrogenous, high-protein enteral nutrition (EN) with 6 g glutamine/L. The authors demonstrated a lack of benefit from IN for the primary end point—the incidence of new infections (53% in the IN group vs 52% in the standard high-protein EN group, P = .96). No benefit was noted for the other end points, including mortality, ventilator days, and ICU and hospital length of stay. Even more surprisingly, they reported increased mortality with IN in the medical ICU patient subgroup at 6-month follow-up (54% in the IN group vs 35% in the EN group, P = .04). MetaPlus adds to mounting evidence challenging the role of aspects of IN in critical illness. As the readers of the Journal of Parenteral and Enteral Nutrition are well aware, the premise of IN is modulation of dysregulated immune responses to achieve a therapeutic benefit. Multiple studies of IN have demonstrated certain improved outcomes in various patient populations, but many were affected by poor selection of control diets, inconsistently defined patient populations, and other methodologic limitations. IN is a broad category that encompasses enteral formulas designed to target disparate physiologic states via 2 distinct mechanistic processes: the first by attenuating excessive inflammatory responses in conditions such as acute respiratory distress syndrome (ARDS) and the second by supplementing conditionally essential nutrients (eg, glutamine, arginine, carnitine) that are rapidly depleted in certain stress states like trauma or surgery. Precise pharmaconutrient recommendations and levels of evidence vary based on disease state.2 The van Zanten et al1 study included mechanically ventilated patients without any characterization of the type of inflammation or dysregulated immune responses such as by measuring C-reactive protein or cytokine levels. Enteral
Journal of Parenteral and Enteral Nutrition Volume XX Number X Month 201X 1–2 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0148607114557133 jpen.sagepub.com hosted at online.sagepub.com
glutamine supplementation was a key aspect of the trial, but the recent REDOX trial demonstrates that high doses of glutamine (administered by both intravenous and enteral routes) in critically ill patients with severe sepsis are associated with lower survival.3 In addition, glutamine is a precursor to arginine, and there are theoretical grounds for concern about the use of arginine in patients with severe sepsis. In light of building doubts about the benefits of individual key “immunonutrients,” we must ask, “When is IN still indicated, and which immunonutrients contribute to improved outcomes?” The authors do not highlight it in the discussion, but in the online supplement to their JAMA article, they provide key subgroup findings as guidance: 6-month survival was reduced in medical ICU patients receiving IN, but there was no difference noted between IN and standard high-protein formula in surgical and trauma patients. This is reasonable given numerous studies suggesting the benefits of IN for surgical patients—but only in the postoperative setting when repletion of conditionally essential nutrients is crucial and not preoperatively as an immune-modulating strategy vs standard high-protein nutrition supplements.4 Collectively, recent data suggest that the immunemodulating nutrients must be individually considered based on mechanism of action, timing and method of use, dosage, and
From 1The Ohio State University, Columbus, Ohio, 2Abbott Nutrition, Research & Development, Columbus, Ohio; and 3Department of Internal Medicine, The Brody School of Medicine–East Carolina University, North Carolina. Financial disclosure: D.C.E. has received educational grants from Nestle Nutrition and Abbott Laboratories and speaking honoraria from Abbott. R.H. is an employee of Abbott Laboratories. Conflicts of interest: D.C.E. is director of nutrition support at The Ohio State University and recipient of educational grants from Abbott Laboratories and Nestle Nutrition and speaking honoraria from Abbott. R.A.H. is medical director at Abbott Nutrition and a full-time employee and shareholder of Abbott Laboratories. Their opinions are based on the literature and science and do not reflect those of their employers. Received for publication September 17, 2014; accepted for publication October 3, 2014. Corresponding Author: Refaat A. Hegazi, MD, PhD, MPH, Research & Development, Abbott Nutrition, 3300 Stelzer Rd, Columbus, OH 43219, USA. Email: [email protected]
Downloaded from pen.sagepub.com at BRIGHAM YOUNG UNIV on January 16, 2015
2
Journal of Parenteral and Enteral Nutrition XX(X)
disease setting. Future trials should focus on patient populations with clear measurable mechanistic derangements of immune function that are amenable to targeted IN strategies rather than a one-size-fits-all therapy broadly applied to all critically ill patients. Modulation of the immune response in the setting of systemic inflammatory response syndrome has been the goal of much research in sepsis, ARDS, trauma, and burn. A variety of drugs have shown promise in basic science and animal models, but in more than 100 human trials, no pharmaceutical therapy has ever emerged as a successful modulator of immune dysfunction of ICU patients.5 In this context, we must be cautious in suggesting that IN may offer the panacea for all critically ill patients. One size may not fit all.
References 1. van Zanten AH, Sztark F, Kaisers UX, et al. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. JAMA. 2014;312(5):514-524. 2. Hegazi RA, Wischmeyer PE. Clinical review: optimizing enteral nutrition for critically ill patients—a simple data-driven formula. Crit Care. 2011;15(6):234. 3. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368(16):1489-1497. 4. Hegazi RA, Hustead DS, Evans DC. Preoperative standard oral nutrition supplements vs immunonutrition: results of a systematic review and metaanalysis [published online June 27, 2014]. J Am Coll Surg. 5. Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20(4):195-203.
Downloaded from pen.sagepub.com at BRIGHAM YOUNG UNIV on January 16, 2015
