Recommendations Summary
CI: Immune-Enhancing Enteral Nutrition and Critical Illness 2006
Click here to see the explanation of recommendation ratings (Strong, Fair, Weak, Consensus, Insufficient Evidence) and labels (Imperative or Conditional). To see more detail on the evidence from which the following recommendations were drawn, use the hyperlinks in the Supporting Evidence Section below.
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Recommendation(s)
CI: Immune-enhancing enteral nutrition
Immune-enhancing EN is not recommended for routine use in critically ill patients in the ICU. Immune-enhancing EN is not associated with reduced infectious complications, LOS, reduced cost of medical care, days on mechanical ventilation or mortality in moderately to less severely ill ICU patients. Their use may be associated with increased mortality in severely ill ICU patients, although adequately-powered trials evaluating this have not been conducted. For the trauma patient, it is not recommended to routinely use immune-enhancing EN, as its use is not associated with reduced mortality, reduced LOS, reduced infectious complications or fewer days on mechanical ventilation.
Rating: Fair
Imperative-
Risks/Harms of Implementing This Recommendation
- Use of immune-enhancing EN in severely ill ICU patients may be associated with increased harm
- There are mixed results and varying interpretations of the efficacy of immune-enhancing EN.
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Conditions of Application
- This recommendation applies to critically ill patients in an ICU setting
- Pharmacological doses of single nutrients were not evaluated, therefore this recommendation only applies to immune-enhancing EN with more than one nutrient.
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Potential Costs Associated with Application
A greater cost is associated with using immune-enhancing EN, compared to standard EN.
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Recommendation Narrative
Mortality
- Seven primary research articles showed no significant effect on mortality with the use of immune-enhancing EN
- Three positive quality RCTs (Atkinson et al, 1998; Caparros et al, 2001; Kieft et al, 2005) and four neutral quality RCTs (Cerra et al, 1990; Moore et al, 1994; Bower et al, 1995; Weimann et al, 1998) agreed that mortality was not statistically impacted by immune-enhancing EN
- The largest positive quality study, a prospective randomized, double-blind controlled intervention study of positive quality (Kieft et al, 2005), with a sample size of 597 ICU patients, showed no effect on mortality.
- Three positive quality RCTs (Atkinson et al, 1998; Caparros et al, 2001; Kieft et al, 2005) and four neutral quality RCTs (Cerra et al, 1990; Moore et al, 1994; Bower et al, 1995; Weimann et al, 1998) agreed that mortality was not statistically impacted by immune-enhancing EN
- In contrast, two studies showed increased mortality with the use of immune-enhancing EN
- A positive quality RCT (Bertolini et al, 2003) with 237 patients showed increased mortality with the use of immune-enhancing EN
- A positive quality prospective double-blind clinical trial (Atkinson et al, 1998), with 390 critically ill patients, showed increased mortality with immune-enhancing EN, although not statistically significant.
- One RCT of positive quality (Galban et al, 2000) demonstrated reduced mortality in critically ill patients who received immune-enhancing EN
- Four positive-quality meta-analyses (Beale et al, 1999; Heyland et al, 2001; Heyland et al, 2003; Montejo et al, 2003) and one neutral quality meta-analysis (Heys et al, 1999) reported no statistically significant effect on mortality for those who received immune-enhancing EN
- Although Heyland et al, 2001, reported no significant effect on mortality, in a subgroup analysis of higher quality studies of critically ill patients, Heyland found an increase in mortality in patients receiving immune-enhancing EN with higher arginine content (RR=2.13; 95% CI=1.08-4.21)
- A meta-analysis of positive quality (Heyland et al, 2001), evaluating critically ill and elective surgical patients reported no significant effect on mortality.
Infectious Complications
- Three primary research articles, one positive quality (Keift, et al, 2005) and two neutral quality (Brown et al, 1994; Weimann et al, 1998) showed no reductions in infectious complications with immune-enhancing EN
- The largest positive quality study, a prospective randomized, double-blind controlled intervention (Kieft et al, 2005) with 597 patients reported no benefit with immune-enhancing EN in reduction of infectious complications.
- Five primary studies, two of positive quality (Galban et al, 2000; Caparros et al, 2001) and three of neutral quality (Moore et al, 1994; Bower et al, 1995; Kudsk et al, 1996) showed fewer infectious complications with the use of immune-enhancing EN
- In the Bower study, infections were decreased only in septic patients who received immune-enhancing EN.
- Five meta-analyses reported mixed results in reducing infectious complications with immune-enhancing EN
- Two positive quality meta-analyses (Heyland et al, 2003; Montejo et al, 2003) reported no significant effect on infectious complications
- Two positive quality meta-analyses (Beale et al, 1999; Heyland et al, 2001) and one neutral quality meta-analysis (Heys et al, 1999) reported significant reductions in infectious complications.
Length of Hospital Stay
- Eight primary research articles showed no reductions in LOS with immune-enhancing EN
- Two positive quality RCTs (Galban et al, 2000; Caparros et al, 2001) reported a higher LOS for the immune-enhancing EN groups, but this was not statistically significant
- Another positive quality RCT (Bertolini et al, 2003) reported no statistically significant difference in LOS among 39 septic patients, although randomization of patients with severe sepsis was stopped early due to increased mortality
- The largest positive quality study, a prospective randomized, double-blind controlled intervention (Kieft et al, 2005) with 597 patients, specifically designed to evaluate ICU LOS, reported no benefit with immune-enhancing EN
- Four neutral quality studies (Cerra et al, 1990; Brown et al, 1994; Moore et al, 1994; Weimann et al, 1998) agreed that LOS was not impacted by immune-enhancing EN.
- Three studies reported reductions in LOS with immune-enhancing EN
- A positive quality RCT (Atkinson et al, 1998) in 390 critically ill patients reported no significant reduction in ICU or LOS for patients receiving immune-enhancing EN
- A subgroup analysis of 101 patients receiving EEN reported significant reductions ICU and LOS.
- A positive quality RCT (Atkinson et al, 1998) in 390 critically ill patients reported no significant reduction in ICU or LOS for patients receiving immune-enhancing EN
- Two neutral quality studies of adult trauma patients (Bower et al, 1995; Kudsk et al, 1996) demonstrated a decreased LOS with immune-enhancing EN
- Four positive quality meta-analyses (Beale et al, 1999; Heyland et al, 2001; Heyland et al, 2003; Montejo et al, 2003) and one neutral quality meta-analysis (Heys et al, 1999) reported significant reductions in LOS for those who received immune-enhancing EN
- It should be noted that all the meta-analyses were conducted prior to publication of the largest positive quality study (Kieft et al, 2005).
Days on Mechanical Ventilation
- A positive quality prospective, double-blind clinical trial (Atkinson et al, 1998) showed that in patients who received adequate nutrition early, a decrease in mechanical ventilation days was shown with immune-enhancing EN
- One positive quality meta-analysis (Heyland et al, 2003) found no difference in mechanical ventilation days
- Two other positive quality meta-analyses (Beale et al, 1999; Montejo et al, 2003) found a significant reduction in mechanical ventilation days
- Four primary research articles, two of positive quality (Galban et al, 2000; Keift et al, 2005) and two of neutral quality (Moore et al, 1994; Weimann et al, 1998) showed no reduction in days on mechanical ventilation with immune-enhancing EN
- One neutral quality PRCT (Kudsk et al, 1996) reported no statistically significant reduction of days on mechanical ventilation
- Although not statistically significant, patients fed immune-enhancing EN had reduced days on mechanical ventilation (2.4 vs. 6.4 days, p = .09).
Cost of Medical Care
- One positive quality meta-analysis (Montejo et al, 2003) found no statistically difference in cost of medical care
- One neutral quality PRCT (Kudsk et al, 1996) of trauma patients showed no differences in medical costs between immune-enhancing EN and standard formulas.
- Seven primary research articles showed no significant effect on mortality with the use of immune-enhancing EN
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Recommendation Strength Rationale
- Trials of immune-enhancing EN have not been designed with a large enough sample size to adequately evaluate mortality
- The population of critically ill adult trauma patients was consistent across the studies included in the evidence analysis
- Conclusion statements are Grade II and III.
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Risks/Harms of Implementing This Recommendation
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Supporting Evidence
The recommendations were created from the evidence analysis on the following questions. To see detail of the evidence analysis, click the blue hyperlinks below (recommendations rated consensus will not have supporting evidence linked).
Does the addition of immune-modulating enteral nutrition to enteral feeding of moderate to less severely ill ICU patients impact mortality?
Does the addition of immune-modulating enteral nutrition to enteral feeding impact length of hospital stay in critically ill ICU patients?
Does the addition of immune-modulating enteral nutrition to enteral feeding impact infectious complications in critically ill ICU patients?
Does the addition of immune-modulating enteral nutrition to enteral feeding impact days on mechanical ventilation in critically ill ICU patients?
Does the addition of immune-modulating enteral nutrition to enteral feeding impact cost of medical care in critically ill ICU patients?
Does the addition of immune-modulating enteral nutrition to enteral feeding of severely ill ICU patients impact mortality?-
References
Atkinson S, Sieffert E, Bihari D. A prospective, randomized, double blind, controlled clinical trial of enteral immunonutrition in the critically ill. Critical Care Medicine, Vol 26(7) July 1998: 1164-1172
Beale RJ, Bryg DJ, Bihari, MB. Immunonutrition in the critically ill: a systematic review of clinical out. Critical Care Med. 1999 vol 27(12) pp 2799-2805
Bertolini G, Iapichino G, Radrizzani D, Facchini B, Simini B, Bruzzone P, Zanforlin G, Tognoni G. Early enteral immunonutrition in patients with severe sepsis. Intensive Care Medicine. 29:834-840, 2003.
Bower, RH, Cerra FB, Bershadsky B, Licari, JJ, Hoyt DB, Jensen GL, Van Buren CT, Rothkpf MM, Daly JM, Adelsberg BR. Early enteral administration of a formula (Impact Registered Trademark) supplemented with arginine, nucleotides, and fish oil intensive care unit patients: Results of a multicenter, prospective, randomized, clinical trial. Critical Care Medicine, Volue 23(3) March 1995 pp 436-449.
Brown RO, Hunt H, Mowatt-Larssen CA, Wojtysiak SL, Henningfield MF, Kudsk KA. Comparison of specialized and standard enteral formulas in trauma patients. Pharmacotherapy. 14(3):314-320, 1994.
Caparros T, Lopez J, Grau T. Early enteral nutrition in critically ill patients with a high-protien diet enriched with arginine, fiber, and antioxidants compared with a standard high-protein diet. The effect on nosocomial infections and outcome. J Parenter Enteral Nutr. 25(6): 299-308. 2001
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. 6(1):84-87, 1990.
Galban, C., Montejo, J.C., Mesejo,P.,Celaya,S., Sandchez-Segura, J., Farre, M., Bryg, D.J., An immune-enhancing enteral diet reduces mortality rate adn episodes of bacterimia in septic intensive care unit patients. Critical Care Medicine, Vol 28(3) pp643-648. 2000.
Heyland DK, Dhaliwal R, Drover JW, et al. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN. 2003; 27: 355-373.
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. (Caring for the critically ill patients). JAMA 2001; 286 p944.
Heys SD, Walker LG, Smith I, Eremin O. Enteral nutritional supplementation with key nutrients in patients with critical illness and cancer; a meta-analysis randomized controlled clinical trials. Annals Surgery, vol 229 (4), 1999 pp467-477.
Kieft H, Roos AN, van Drunen JDE, Bindels AJGH, Bindels JG, Hofman Z. Clinical outcomes of immunonutrition in a heterogeneous intensive care population. Intensive Care Med (2005) 31:524-532.
Kudsk KA, Minard G, Croce MA, Brown RO. Lowrey TS, Pritchard FE, Dickerson RN, Fabian TC. A randomized trial of isonitrogenous enteral diets after severe trauma: an immune-enhancing diet reduces septic complications. Ann Surg. 1996: 224 (4); 531-543.
Montejo JC, Zarazaga A, Lopez-Martinez J, Urrutia G, Roque M, Blesa AL, Celaya S, Conejero R, Galban C, Garcia de Lorenzo A, Grau T, Mesejo A, Ortiz-Leyba C, Planas M, Ordonez J, Jimenez FJ. Immunonutrition in the intensive care unit. A systematic review and consensus statement. Clinical Nutrition. 22(3):221-233, 2003.
Moore FA, Moore EE, Kudsk KA, Brown RO, Bower RH, Koruda MJ, Baker CC, Barbul A. Clinical benefits of an immune-enhancing diet for early post injury enteral feeding. J Trauma 37:607-615, 1994.
Weimann A, Bastian L, Bischoff W, Grotz M, Hansel M, Lotz J, Trautwein C, Tusch G, Schlitt HJ, Regel G. Influence of Arginine, Omega-3 Fatty Acids and Nucleotide-Supplemented Enteral Support on Systemic Inflammatory Response Syndrome and Multiple Organ Failure in Patients After Sever Trauma. Nutrition 14:165-172, 1998.
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References