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Editorial |

Immunonutrition in Critical Illness:  Limited Benefit, Potential Harm FREE

Todd W. Rice, MD, MSc1
[+] Author Affiliations
1Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
JAMA. 2014;312(5):490-491. doi:10.1001/jama.2014.7699.
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Published online

Many critically ill patients are unable to provide their own nourishment. Artificial nutrition has become a routine part of critical care, and when possible, enteral is preferred over parenteral nutrition. Since its inception, many specialty enteral formulas have been developed for specific disease states. For example, higher-protein, lower-volume, higher-osmolar formulas with little to no potassium are designed for patients with kidney failure and fat-free elemental enteral formulas are often used for severe pancreatitis. One class of specialty formulas is called immunonutrition, which describe formulas designed to alter or attenuate the immune and inflammatory response seen in critical illness. These formulas may contain omega-3 fatty acids, potentially less inflammatory than the omega-6 fatty acids, essential amino acids such as arginine or glutamine, and antioxidants.

Meta-analyses suggest that immunonutrition is associated with a reduction in the development of infectious complications in critically ill patients.1,2 However, recent large studies have failed to demonstrate benefit and sometimes even found harm with the use of immunonutrition in critically ill patients. The Scottish Intensive Care Glutamine or Selenium Evaluative Trial (SIGNET) study3 found no benefit on infection development or mortality for either parenteral glutamine or selenium supplementation to parenteral nutrition in critically ill patients. Similarly, the Reducing Deaths Due to Oxidative Stress (REDOX) study4 found no benefit to enteral and parenteral selenium supplementation and higher mortality in critically ill patients who received combined enteral and parenteral glutamine supplementation. Although post hoc analysis suggested the detrimental effect was greatest in patients with multisystem organ dysfunction and renal failure,5 any potential harm of glutamine might have resulted from the high doses administered, including supplementing enteral administration with parenteral, in patients who were not glutamine deficient at baseline. Additionally, the OMEGA study found increased mortality in patients with acute respiratory distress syndrome (ARDS) whose enteral feeding was supplemented with omega-3 fatty acids, γ-linolenic acid, and antioxidants.6 Critics of the OMEGA trial pointed to the supplements being given via twice daily bolus administration and higher protein in the control group as potential explanations for the results.7

In this issue of JAMA, van Zanten and colleagues8 report the results of the MetaPlus trial. Although designed to evaluate the effect of enteral immunonutrition on the development of infectious complications in critically ill patients, the MetaPlus trial also provides important information in interpreting the results and answering critiques of the REDOX and OMEGA trials. In this rigorously conducted trial, 301 patients were randomized to receive an experimental high-protein enteral nutrition formula enriched with omega-3 fatty acids, glutamine, selenium, and other antioxidants vs a commercially available high-protein enteral formula. The 2 formulas were isonitrogenous and isocaloric with the experimental formula containing slightly more fat (in the form of omega-3 fatty acids and medium-chain triglycerides) in lieu of some carbohydrate (141 vs 231 g per 1500 mL). The experimental formula was also enriched with glutamine, vitamins C and E, and about twice as much selenium.

The study has numerous strengths. It was adequately blinded, which is important given that the study personnel determined the primary end point of infectious complications. Infections were defined according to Centers for Disease Control and Prevention criteria and prospectively collected, which may have raised investigator awareness to fever, leukocytosis, or new initiation of antibiotics. This may at least partially explain the relatively high incidence of nosocomial infections, more than twice what the authors anticipated. Instead of enrolling a subset of patients with a specific disease, the trial enrolled a heterogeneous critically ill population expected to require mechanical ventilation for at least 72 hours. Although screening failures were not systematically collected, the baseline demographics suggest that a fairly representative critically ill population was enrolled. About 20% of the patients had sepsis, half were enrolled from surgical intensive care units (ICUs), and a third were from medical ICUs. Patients in both groups received 70% to 80% of their daily goal calories via enteral feeding with little supplemental parenteral nutrition used to confound possible results.

The immune-enhanced high-protein formula did not decrease the number of infectious complications compared with a standard high-protein enteral formula (53% vs 52%, respectively). Likewise, this intervention did not reduce ICU or hospital mortality, duration of mechanical ventilation, or ICU or hospital lengths of stay. Although limited by small numbers, these negative results were consistent across all subgroups examined by the authors.

Like the REDOX and OMEGA trials, the immunonutrition group in the MetaPlus trial also had statistically higher longer-term mortality, (54% vs 35% 6-month mortality) especially in the medical ICU subgroup.8 However, unlike REDOX, all immunonutrition (including glutamine and selenium) in the MetaPlus trial was administered enterally and at lower dosages. Similarly, unlike OMEGA, the immunonutrition formula used in the MetaTrial was isonitrogenous and administered as a continuous enteral infusion. Despite administering lower levels of glutamine, selenium, and omega-3 fatty acids overall than the SIGNET, REDOX, and OMEGA trials,3,4,6 the consistency of the results across these studies suggests potential harm in administering immunonutrition to a broad population of critically ill patients.

Despite reasonable mechanistic rationale, why has immunonutrition failed to improve outcomes in recent large, multicenter studies in critically ill patients? The answer is likely multifactorial. Timing of administration may play a role. 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. In fact, some data suggest that preinjury or preillness administration of immunonutrition may improve outcomes.9,10 However, other recent studies have failed to demonstrate benefit from “preemptive” immunonutrition supplements.11,12 Additionally, enteral immunonutrition may not actually have immunomodulatory effects. Although markers of inflammation or oxidative stress were not measured in MetaPlus, enteral immunonutrition failed to alter these markers in the ARDS Network OMEGA study despite adequate absorption of omega-3 fatty acids into the serum.6 Parenteral administration of glutamine and selenium failed to improve outcomes in SIGNET3 and REDOX,4 yet recent preliminary studies of parenteral omega-3 fatty acids have demonstrated encouraging results, but need further study.13 This is especially important in light of the recent negative and potentially harmful results seen in recent trials of enteral immunonutrition. “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.

What is the next step for immunonutrition in critical illness? Is the promise seen with the sound biological rationale and boosted by the initial encouraging results gone? The results of the MetaTrial study, in conjunction with those of SIGNET, REDOX, and OMEGA suggest that the initial promise seen with these agents has not been fulfilled and that combined immunonutrition is not beneficial and may be potentially harmful, when used routinely in a heterogeneous population of critically ill patients. However, many questions surrounding immunonutrition remain unanswered. Are there specific critically ill populations that may benefit from some immunomodulation or supplementation of individual immunomodulating agents, such as glutamine supplementation in burns or vitamin D replacement in severe sepsis? Does administration of multiple potential immunologic modulating agents together alter the individual effects of each agent? Combined administration in a single formula or supplement in all of these trials prevents implicating any single component (ie, omega-3 fatty acids, glutamine, or antioxidants). In addition, enteral and parenteral administration may result in differential effects. Although these uses of immunomodulating nutrition still need to be explored, 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.

ARTICLE INFORMATION

Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.

Corresponding Author: Todd W. Rice, MD, MSc, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, TN 37232-2650 (todd.rice@vanderbilt.edu).

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Heyland  DK, Novak  F, Drover  JW, Jain  M, Su  X, Suchner  U.  Should immunonutrition become routine in critically ill patients? a systematic review of the evidence. JAMA. 2001;286(8):944-953.
PubMed   |  Link to Article
Montejo  JC, Zarazaga  A, López-Martínez  J,  et al; Spanish Society of Intensive Care Medicine and Coronary Units.  Immunonutrition in the intensive care unit: a systematic review and consensus statement. Clin Nutr. 2003;22(3):221-233.
PubMed   |  Link to Article
Andrews  PJ, Avenell  A, Noble  DW, Campbell  MK, Croal  BL, Simpson  WG,  et al Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ. 2011;342:d1542.
PubMed   |  Link to Article
Heyland  D, Muscedere  J, Wischmeyer  PE,  et al; Canadian Critical Care Trials Group.  A randomized trial of glutamine and antioxidants in critically ill patients [published correction appears in N Engl J Med. 2013;368(19):1853]. N Engl J Med. 2013;368(16):1489-1497.
PubMed   |  Link to Article
Heyland  DK, Elke  G, Cook  D,  et al; on behalf of the Canadian Critical Care Trials Group.  Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial [published online May 5, 2014]. JPEN J Parenter Enteral Nutr. 2014.
PubMed
Rice  TW, Wheeler  AP, Thompson  BT, deBoisblanc  BP, Steingrub  J, Rock  P; NIH NHLBI Acute Respiratory Distress Syndrome Network of Investigators.  Enteral omega-3 fatty acid, γ-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306(14):1574-1581.
PubMed   |  Link to Article
Felbinger  TW, Weigand  MA, Mayer  K.  Supplementation in acute lung injury. JAMA. 2012;307(2):144-146.
PubMed   |  Link to Article
van Zanten  ARH, 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. doi:10.1001/jama.2014.7698.
Braga  M, Wischmeyer  PE, Drover  J, Heyland  DK.  Clinical evidence for pharmaconutrition in major elective surgery. JPEN J Parenter Enteral Nutr. 2013;37(5)(suppl):66S-72S.
PubMed   |  Link to Article
Pontes-Arruda  A, Martins  LF, de Lima  SM,  et al; Investigating Nutritional Therapy with EPA, GLA and Antioxidants Role in Sepsis Treatment (INTERSEPT) Study Group.  Enteral nutrition with eicosapentaenoic acid, γ-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT study. Crit Care. 2011;15(3):R144.
PubMed   |  Link to Article
Kowey  PR, Reiffel  JA, Ellenbogen  KA, Naccarelli  GV, Pratt  CM.  Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA. 2010;304(21):2363-2372.
PubMed   |  Link to Article
Kromhout  D, Giltay  EJ, Geleijnse  JM; Alpha Omega Trial Group.  n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363(21):2015-2026.
PubMed   |  Link to Article
Manzanares  W, Dhaliwal  R, Jurewitsch  B, Stapleton  RD, Jeejeebhoy  KN, Heyland  DK.  Parenteral fish oil lipid emulsions in the critically ill: a systematic review and meta-analysis. JPEN J Parenter Enteral Nutr. 2014;38(1):20-28.
PubMed   |  Link to Article

Figures

Tables

References

Heyland  DK, Novak  F, Drover  JW, Jain  M, Su  X, Suchner  U.  Should immunonutrition become routine in critically ill patients? a systematic review of the evidence. JAMA. 2001;286(8):944-953.
PubMed   |  Link to Article
Montejo  JC, Zarazaga  A, López-Martínez  J,  et al; Spanish Society of Intensive Care Medicine and Coronary Units.  Immunonutrition in the intensive care unit: a systematic review and consensus statement. Clin Nutr. 2003;22(3):221-233.
PubMed   |  Link to Article
Andrews  PJ, Avenell  A, Noble  DW, Campbell  MK, Croal  BL, Simpson  WG,  et al Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ. 2011;342:d1542.
PubMed   |  Link to Article
Heyland  D, Muscedere  J, Wischmeyer  PE,  et al; Canadian Critical Care Trials Group.  A randomized trial of glutamine and antioxidants in critically ill patients [published correction appears in N Engl J Med. 2013;368(19):1853]. N Engl J Med. 2013;368(16):1489-1497.
PubMed   |  Link to Article
Heyland  DK, Elke  G, Cook  D,  et al; on behalf of the Canadian Critical Care Trials Group.  Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial [published online May 5, 2014]. JPEN J Parenter Enteral Nutr. 2014.
PubMed
Rice  TW, Wheeler  AP, Thompson  BT, deBoisblanc  BP, Steingrub  J, Rock  P; NIH NHLBI Acute Respiratory Distress Syndrome Network of Investigators.  Enteral omega-3 fatty acid, γ-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306(14):1574-1581.
PubMed   |  Link to Article
Felbinger  TW, Weigand  MA, Mayer  K.  Supplementation in acute lung injury. JAMA. 2012;307(2):144-146.
PubMed   |  Link to Article
van Zanten  ARH, 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. doi:10.1001/jama.2014.7698.
Braga  M, Wischmeyer  PE, Drover  J, Heyland  DK.  Clinical evidence for pharmaconutrition in major elective surgery. JPEN J Parenter Enteral Nutr. 2013;37(5)(suppl):66S-72S.
PubMed   |  Link to Article
Pontes-Arruda  A, Martins  LF, de Lima  SM,  et al; Investigating Nutritional Therapy with EPA, GLA and Antioxidants Role in Sepsis Treatment (INTERSEPT) Study Group.  Enteral nutrition with eicosapentaenoic acid, γ-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT study. Crit Care. 2011;15(3):R144.
PubMed   |  Link to Article
Kowey  PR, Reiffel  JA, Ellenbogen  KA, Naccarelli  GV, Pratt  CM.  Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA. 2010;304(21):2363-2372.
PubMed   |  Link to Article
Kromhout  D, Giltay  EJ, Geleijnse  JM; Alpha Omega Trial Group.  n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363(21):2015-2026.
PubMed   |  Link to Article
Manzanares  W, Dhaliwal  R, Jurewitsch  B, Stapleton  RD, Jeejeebhoy  KN, Heyland  DK.  Parenteral fish oil lipid emulsions in the critically ill: a systematic review and meta-analysis. JPEN J Parenter Enteral Nutr. 2014;38(1):20-28.
PubMed   |  Link to Article

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