Should Immunonutrition Become Routine in Critically Ill Patients? A Systematic Review of the Evidence | Critical Care Medicine | JAMA | JAMA Network
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1.
Heyland DK, Cook DJ, Griffith L, Keenan SP, Brun-Buisson C.for the Canadian Critical Trials Group.  The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient.  Am J Respir Crit Care Med.1999;159:1249-1256.Google Scholar
2.
Digiovine B, Chenoweth C, Watts C, Higgins M. The attributable mortality and costs of primary nosocomial bloodstream infections in the intensive care unit.  Am J Respir Crit Care Med.1999;160:976-981.Google Scholar
3.
Fagon JY, Novara A, Stephan F, Girou E, Safar M. Mortality attributable to nosocomial infections in the ICU.  Infect Control Hosp Epidemiol.1994;15:428-434.Google Scholar
4.
Dempsey DT, Mullen JL, Buzby GP. The link between nutritional status and clinical outcome: can nutritional intervention modify it?  Am J Clin Nutr.1988;47(suppl 2):352-356.Google Scholar
5.
Heyland DK, MacDonald S, Keefe L, Drover JW. Total parenteral nutrition in the critically ill patient: a meta-analysis.  JAMA.1998;280:2013-2019.Google Scholar
6.
Evoy D, Lieberman MD, Fahey TJ, Daly JM. Immunonutrition: the role of arginine.  Nutrition.1998;14:611-617.Google Scholar
7.
Wilmore DW, Shabert JK. Role of glutamine in immunologic responses.  Nutrition.1998;14:618-626.Google Scholar
8.
Hall JC, Heel K, McCauley R. Glutamine.  Br J Surg.1996;83:305-312.Google Scholar
9.
Leleiko NS, Walsh MJ. Dietary purine nucleotides and the gastrointestinal tract.  Nutrition.1995;11:725-730.Google Scholar
10.
Alexander JW. Immunonutrition: the role of omega-3 fatty acids.  Nutrition.1998;14:627-633.Google Scholar
11.
Wu D, Meydani SN. n-3 polyunsaturated fatty acids and immune function.  Proc Nutr Soc.1998;57:503-509.Google Scholar
12.
Heys SD, Walker LG, Smith I, Eremin O. Enteral nutritional supplementation with key nutrients in patients with critical illness and cancer: a meta-analysis of randomized controlled clinical trials.  Ann Surg.1999;229:467-477.Google Scholar
13.
Beale RJ, Bryg DJ, Bihari DJ. Immunonutrition in the critically ill: a systematic review of clinical outcome.  Crit Care Med.1999;27:2799-2805.Google Scholar
14.
Gregoire G, Derderian F, Le Lorier J. Selecting the language of the publications included in a meta-analysis: is there a Tower of Babel bias?  J Clin Epidemiol.1995;48:159-163.Google Scholar
15.
Atkinson S, Sieffert E, Bihari D.for the Guy's Hospital Intensive Care Group.  A prospective, randomized, double-blind, controlled clinical trial of enteral immunonutrition in the critically ill.  Crit Care Med.1998;26:1164-1172.Google Scholar
16.
Galban C, Montejo JC, Mesejo A.  et al.  An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients.  Crit Care Med.2000;28:643-648.Google Scholar
17.
Braga M, Gianotti L, Vignali A, Cestari A, Bisagni P, Di Carlo V. Artificial nutrition after major abdominal surgery: impact of route of administration and composition of the diet.  Crit Care Med.1998;26:24-30.Google Scholar
18.
Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials.  JAMA.1995;273:408-412.Google Scholar
19.
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled?  Ann Intern Med.1996;125:605-613.Google Scholar
20.
Wilmore DW. Catabolic illness: strategies for enhancing recovery.  N Engl J Med.1991;325:695-702.Google Scholar
21.
Lorente JA, Landin L, De Pablo R, Renes E, Liste D. L-arginine pathway in the sepsis syndrome.  Crit Care Med.1993;21:1287-1295.Google Scholar
22.
Naylor AF. Small sample considerations in combining 2 × 2 tables.  Biometrics.1967;23:349-356.Google Scholar
23.
Rothman JR. Modern Epidemiology. Boston, Mass: Little Brown & Co Inc; 1986.
24.
Rothman KJ, Boice JD. Epidemiological Analysis With a Programmable Calculator. Washington, DC: National Institutes of Health; 1979.
25.
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials.1986;7:177-188.Google Scholar
26.
Whitehead A, Whitehead J. A general parametric approach to the meta-analysis of randomized clinical trials.  Stat Med.1991;10:1665-1677.Google Scholar
27.
Gianotti L, Braga M, Vignali A.  et al.  Effect of route of delivery and formulation of postoperative nutritional support in patients undergoing major operations for malignant neoplasms.  Arch Surg.1997;132:1222-1229.Google Scholar
28.
Schilling J, Vranjes N, Fierz W.  et al.  Clinical outcome and immunology of postoperative arginine, omega-3 fatty acids, and nucleotide-enriched enteral feeding: a randomized prospective comparison with standard enteral and low calorie/low fat IV solutions.  Nutrition.1996;12:423-429.Google Scholar
29.
Braga M, Vignali A, Gianotti L, Cestari A, Profili M, Carlo VD. Immune and nutritional effects of early enteral nutrition after major abdominal operations.  Eur J Surg.1996;162:105-112.Google Scholar
30.
Hedges LV. Estimation of effect size from a series of independent experiments.  Psychol Bull.1982;92:490-499.Google Scholar
31.
Daly JM, Lieberman MD, Goldfine J.  et al.  Enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids in patients after operation: immunologic, metabolic, and clinical outcome.  Surgery.1992;112:56-67.Google Scholar
32.
Daly JM, Weintraub FN, Shou J, Rosato EF, Lucia M. Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients.  Ann Surg.1995;221:327-338.Google Scholar
33.
Senkal M, Mumme A, Eickhoff U.  et al.  Early postoperative enteral immunonutrition: clinical outcome and cost-comparison analysis in surgical patients.  Crit Care Med.1997;25:1489-1496.Google Scholar
34.
Braga M, Gianotti L, Radaelli G.  et al.  Perioperative immunonutrition in patients undergoing cancer surgery: results of a randomized double-blind phase 3 trial.  Arch Surg.1999;134:428-433.Google Scholar
35.
Senkal M, Zumtobel V, Bauer KH.  et al.  Outcome and cost-effectiveness of perioperative enteral immunonutrition in patients undergoing elective upper gastrointestinal tract surgery: a prospective randomized study.  Arch Surg.1999;134:1309-1316.Google Scholar
36.
Snyderman CH, Kachman K, Molseed L.  et al.  Reduced postoperative infections with an immune-enhancing nutritional supplement.  Laryngoscope.1999;109:915-921.Google Scholar
37.
Gottschlich MM, Jenkins M, Warden GD.  et al.  Differential effects of three enteral dietary regimens on selected outcome variables in burn patients.  JPEN J Parenter Enteral Nutr.1990;14:225-236.Google Scholar
38.
Brown RO, Hunt H, Mowatt-Larssen CA, Wojtysiak SL, Henningfield MF, Kudsk KA. Comparison of specialized and standard enteral formulas in trauma patients.  Pharmacotherapy.1994;14:314-320.Google Scholar
39.
Moore FA, Moore EE, Kudsk KA.  et al.  Clinical benefits of an immune-enhancing diet for early postinjury enteral feeding.  J Trauma.1994;37:607-615.Google Scholar
40.
Kudsk KA, Minard G, Croce MA.  et al.  A randomized trial of isonitrogenous enteral diets after severe trauma: an immune-enhancing diet reduces septic complications.  Ann Surg.1996;224:531-540.Google Scholar
41.
Engel JM, Menges T, Neuhauser C, Schaefer B, Hempelmann G. Effects of various feeding regimens in multiple trauma patients on septic complications and immune parameters [in German].  Anasthesiol Intensivmed Notfallmed Schmerzther.1997;32:234-239.Google Scholar
42.
Mendez C, Jurkovich GJ, Garcia I, Davis D, Parker A, Maier RV. Effects of an immune-enhancing diet in critically injured patients.  J Trauma.1997;42:933-940.Google Scholar
43.
Weimann A, Bastian L, Bischoff WE.  et al.  Influence of arginine, omega-3 fatty acids and nucleotide-supplemented enteral support on systemic inflammatory response syndrome and multiple organ failure in patients after severe trauma.  Nutrition.1998;14:165-172.Google Scholar
44.
Cerra FB, Lehman S, Konstantinides N, Konstantinides F, Shronts EP, Holman R. Effect of enteral nutrient on in vitro tests of immune function in ICU patients: a preliminary report.  Nutrition.1990;6:84-87.Google Scholar
45.
Bower RH, Cerra FB, Bershadsky B.  et al.  Early enteral administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: results of a multicenter, prospective, randomized, clinical trial.  Crit Care Med.1995;23:436-449.Google Scholar
46.
Rodrigo CM, Garcia PJ. The effect of the composition of the enteral nutrition on infection in the critical patient [in Spanish].  Nutr Hosp.1997;12:80-84.Google Scholar
47.
Heslin MJ, Latkany L, Leung D.  et al.  A prospective, randomized trial of early enteral feeding after resection of upper gastrointestinal malignancy.  Ann Surg.1997;226:567-577.Google Scholar
48.
Saffle JR, Wiebke G, Jennings K, Morris SE, Barton RG. Randomized trial of immune-enhancing enteral nutrition in burn patients.  J Trauma.1997;42:793-800.Google Scholar
49.
Morais AA, Santos JE, Faintuch J. Comparative study of arginine and glutamine supplements in malnourished surgical patients [in Spanish].  Rev Hosp Clin Fac Med Sao Paulo.1995;50:276-279.Google Scholar
50.
Daly JM, Reynolds J, Sigal RK, Shou J, Liberman MD. Effect of dietary protein and amino acids on immune function.  Crit Care Med.1990;18:S86-S93.Google Scholar
51.
Houdijk AP, Rijnsburger ER, Jansen J.  et al.  Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma.  Lancet.1998;352:772-776.Google Scholar
52.
Kenler AS, Swails WS, Driscoll DF.  et al.  Early enteral feeding in postsurgical cancer patients: fish oil structured lipid-based polymeric formula versus a standard polymeric formula.  Ann Surg.1996;223:316-333.Google Scholar
53.
Jones C, Palmer TE, Griffiths RD. Randomized clinical outcome study of critically ill patients given glutamine-supplemented enteral nutrition.  Nutrition.1999;15:108-115.Google Scholar
54.
Preiser JC, Vincent JL, Carpentier YA. Effects of enteral feeding supplementation with arginine and vitamins A, C and E in critically ill patients.  Crit Care Med.1998;26:A91.Google Scholar
55.
Gadek JE, DeMichele SJ, Karlstad MD.  et al. for the Enteral Nutrition in ARDS Study Group.  Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome.  Crit Care Med.1999;27:1409-1420.Google Scholar
56.
Houdijk AP, Nijveldt RJ, van Leeuwen PA. Glutamine-enriched enteral feeding in trauma patients: reduced infectious morbidity is not related to changes in endocrine and metabolic responses.  JPEN J Parenter Enteral Nutr.1999;23:S52-S58.Google Scholar
57.
Braga M, Vignali A, Gianotti L, Cestari A, Profili M, Di Carlo V. Benefits of early postoperative enteral feeding in cancer patients [in Italian].  Infusionsther Transfusionsmed.1995;22:280-284.Google Scholar
58.
Lieberman MD, Shou J, Torres AS.  et al.  Effects of nutrient substrates on immune function.  Nutrition.1990;6:88-91.Google Scholar
59.
Gianotti L, Braga M, Vignali A, Bisagni P, Di Carlo V. Route and composition of postoperative nutritional support: impact on immune-metabolic response and postoperative outcome [in Italian].  Rivista Italiana di Nutrizione Parenterale ed Enterale.1998;16:173-182.Google Scholar
60.
Bastian L, Weimann A, Regel G, Tscherne H. Is modification of systemic inflammatory response syndrome and multiple organ failure by parenteral feeding possible [in German]?  Langenbecks Arch Chir Suppl Kongressbd.1998;115:1083-1085.Google Scholar
61.
Bastian L, Weimann A, Bischoff W.  et al.  Clinical effects of supplemental enteral nutrition solution in severe polytrauma [in German].  Unfallchirurg.1998;101:105-114.Google Scholar
62.
Di Carlo V, Gianotti L, Balzano G, Zerbi A, Braga M. Complications of pancreatic surgery and the role of perioperative nutrition.  Dig Surg.1999;16:320-326.Google Scholar
63.
Braga M, Gianotti L, Balzano G.  et al.  Artificial nutrition after major pancreatic resection: results of a prospective randomized clinical trial.  JPEN J Parenter Enteral Nutr.1999;23:S2.Google Scholar
64.
Gianotti L, Braga M, Balzano G, Zerbi A, Gentilini O, Di Carlo V. Artificial nutrition after pancreaticoduodenectomy.  Pancreas.2000;21:344-351.Google Scholar
65.
Talabiska DG, Fish J, Gianferante L, Jensen GL. A modified enteral formula may reduce infectious complications in elderly intensive care patients.  FASEB J.1993;7:A378.Google Scholar
66.
Hasselmann M, Kummerlen CH, Bryg DJ.  et al.  Enteral feeding supplemented with arginine, fish oil and nucleotides (Impact) reduces infection rate and improves immunitary status in critically ill patients.  Intensive Care Med.1997;23:S136.Google Scholar
67.
Chendrasekhar A, Fagerli JC, Prabhakar G, Landreth K, Timbertake GA. Evaluation of an enhanced diet in patients with severe closed head injury.  Crit Care Med.1997;25:A135.Google Scholar
68.
Tepaske R, Eysman L, van Deventer S, Ince C, Stoutenbeekt CP, Kesecioglu J. Perioperative immunonutrition in "high risk" cardiac surgery patients improves immunological parameters and clinical outcome.  EUSIS-Kongres Oslo.1999.Google Scholar
69.
Braga M, Gianotti L, Cestari A.  et al.  Gut function and immune and inflammatory responses in patients perioperatively fed with supplemented enteral formulas.  Arch Surg.1996;131:1257-1264.Google Scholar
70.
Braga M, Gianotti L, Vignali A, Di Carlo V. Immunonutrition in gastric cancer surgical patients.  Nutrition.1998;14:831-835.Google Scholar
71.
Gianotti L, Braga M, Fortis C.  et al.  A prospective, randomized clinical trial on perioperative feeding with an arginine-, omega-3 fatty acid-, and RNA-enriched enteral diet: effect on host response and nutritional status.  JPEN J Parenter Enteral Nutr.1999;23:314-320.Google Scholar
72.
Saito H, Trocki O, Wang SL, Gonce SJ, Joffe SN, Alexander JW. Metabolic and immune effects of dietary arginine supplementation after burn.  Arch Surg.1987;122:784-789.Google Scholar
73.
Gonce SJ, Peck MD, Alexander JW, Miskell PW. Arginine supplementation and its effect on established peritonitis in guinea pigs.  JPEN J Parenter Enteral Nutr.1990;14:237-244.Google Scholar
74.
Meakins JL, Christou NV, Shizgal HM, MacLean LD. Therapeutic approaches to anergy in surgical patients: surgery and levamisole.  Ann Surg.1979;190:286-296.Google Scholar
75.
Ogawa K, Hirai M, Katsube T.  et al.  Suppression of cellular immunity by surgical stress.  Surgery.2000;127:329-336.Google Scholar
Caring for the Critically Ill Patient
August 22/29, 2001

Should Immunonutrition Become Routine in Critically Ill Patients?A Systematic Review of the Evidence

Author Affiliations

Author Affiliations: Departments of Medicine (Drs Heyland and Novak) and Surgery (Drs Drover and Jain), Queen's University, Kingston General Hospital, Kingston, Ontario; and Department of Anesthesiology, Grosshadern University Hospital, Ludwig Maximilian's University, Munich, Germany (Dr Suchner). Dr Su works in Munich, Germany. Dr Suchner is now employed by Fresenius-Kabi, Munich, Germany.

 

Caring for the Critically Ill Patient Section Editor: Deborah J. Cook, MD, Consulting Editor, JAMA

JAMA. 2001;286(8):944-953. doi:10.1001/jama.286.8.944
Abstract

Context Several nutrients have been shown to influence immunologic and inflammatory responses in humans. Whether these effects translate into an improvement in clinical outcomes in critically ill patients remains unclear.

Objective To examine the relationship between enteral nutrition supplemented with immune-enhancing nutrients and infectious complications and mortality rates in critically ill patients.

Data Sources The databases of MEDLINE, EMBASE, Biosis, and CINAHL were searched for articles published from 1990 to 2000. Additional data sources included the Cochrane Controlled Trials Register from 1990 to 2000, personal files, abstract proceedings, and relevant reference lists of articles identified by database review.

Study Selection A total of 326 titles, abstracts, and articles were reviewed. Primary studies were included if they were randomized trials of critically ill or surgical patients that evaluated the effect of enteral nutrition supplemented with some combination of arginine, glutamine, nucleotides, and omega-3 fatty acids on infectious complication and mortality rates compared with standard enteral nutrition, and included clinically important outcomes, such as mortality.

Data Extraction Methodological quality of individual studies was scored and necessary data were abstracted in duplicate and independently.

Data Synthesis Twenty-two randomized trials with a total of 2419 patients compared the use of immunonutrition with standard enteral nutrition in surgical and critically ill patients. With respect to mortality, immunonutrition was associated with a pooled risk ratio (RR) of 1.10 (95% confidence interval [CI], 0.93-1.31). Immunonutrition was associated with lower infectious complications (RR, 0.66; 95% CI, 0.54-0.80). Since there was significant heterogeneity across studies, we examined several a priori subgroup analyses. We found that studies using commercial formulas with high arginine content were associated with a significant reduction in infectious complications and a trend toward a lower mortality rate compared with other immune-enhancing diets. Studies of surgical patients were associated with a significant reduction in infectious complication rates compared with studies of critically ill patients. In studies of critically ill patients, studies with a high-quality score were associated with increased mortality and a significant reduction in infectious complication rates compared with studies with a low-quality score.

Conclusion Immunonutrition may decrease infectious complication rates but it is not associated with an overall mortality advantage. However, the treatment effect varies depending on the intervention, the patient population, and the methodological quality of the study.

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