CI: Immune-Modulating Enteral Nutrition (2006)

Study Design:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To systematically review, critically appraise, and synthesize randomized clinical trial data evaluating the effect of enteral immunonutrients in critically ill patients.       
Inclusion Criteria:
  • Randomized clinical trials that studied critically ill or surgical patients compared enteral nutrition supplemented with a combination of 2 or more of the 4 most frequently used immune-enhancing agents (arginine, glutamine, omega-3 fatty acids, or nucleotides compared) with standard enteral nutrition, and included clinically important outcomes, such as mortality, infectious complications and length of stay.
  • Defined critically ill patients as being routinely cared for in a critical-care environment, including studies wiht elective surgical patients.    
Exclusion Criteria:
  • Non-randomized clinical control trials
  • Studies reporting only nutritional or immunological outcomes
Description of Study Protocol:


  • Computerized searches for studies were identified using text word or MeSH terms: randomized, blind, clincial trial, nutrition, arginine, glutamine, omega-3 fatty acids, fish oil, nucleotides, immune, and immunonutrition on MEDLINE, EMBASE, Biosis, and CINHAL electronic database from 1990 to 2000 and the Cochrane Controlled Trials Register from 1990 to 2000
  • Major manufactureers of "immune-enhanced" formulas were contacted for additional published and unpublished studies.
  • Reference lists of review and original articles, personal files, and abstract proceedings of recent scientific meetings were also searched.
  • All primary studies were retrieved and reviewed independently by two principle investigators.
  • Methodological quality was assessed by using 9 parameters to provide a score (0-14 with 14 designated as higher quality).
  • Tested for heterogeneity (between –study differences in treatment effect) by the following subgroup analyses:

    • Compare studies with higher methodological scores (> 8) to those with lower scores (<8).

    • Compare high arginine formulas (Impact and Immunoaid) with other formulations (which contain less arginine) in critically ill patients with infection and sepsis.

    • Compare studies of elective surgical patients with critically ill.


Data Collection Summary:

Primary Outcomes:

  • Mortality
  • Number of patients with new infectious complications (pneumonia, intra-abdominal abscess, sepsis, line sepsis, wound infection, and urinary tract infection

Secondary Outcomes:

  • Length of hospital and ICU stay
  • Duration of mechanical ventilation

Data was combined from all studies to estimate common risk ratio and associated 95% confidence intervals.

Description of Actual Data Sample:

  • 326 citations were identified
  • 22 randomized trials met all inclusion criteria
  • 2419 patients that compared the use of immune-enhanced enteral formula with standard formulas.
Summary of Results:

Aggregate results:

  • Immunonutrition was associated with no mortality advantage (RR, 1.10; 95% CI, 0.93-1.31), test for heterogeneity was not significant (P=0.54).
  • In the 18 studies that reported infectious complications—immunonutrition was associated with fewer patients with infectious complications compared with standard formulas (RR, 0.66; 95% CI, 0.54-0.80), the test for heterogeneity was significant (P<.001)
  • In the 17 studies that reported length of stay, patients receiving immunonutrition had a shorter length of hospital stay (Effect Size, -0.63; 95% CI, -.94 to -.32), test for heterogeneity was significant (P<.001) Using pooled differences between 2 groups, hospital stay was shorter (-3.33 days; 95% CI, -5.63 to 1.02 days)

Subgroup analyses:

  • High arginine formulas vs. low arginine formulas—no difference between the subgroups in mortality rate (P= 0.06).
  • High arginine studies showed no difference in mortality rate (RR 1,05; 95% CI, 0.88-1.25).
  • Subgroup fed lower arginine content higher mortality rate (RR 2.13; 95% CI, 1.09-4.21).
  • Rate of infectious complications was significantly lower in patients receiving formulas with high arginine content (RR 0.55; 95% CI 0.46-0.67)
  • No difference in the subgroup of formulas other than formulas with high arginine content (RR, 1.27; 95% CI 0.74-2.22).
  • Higher arginine formulas were associated with shorter hospital stay.

  • In studies of critically ill patients, immunonutrition had no effect on infectious complications. In elective surgery patients, the number of patients with an infectious complications was significantly lower (RR, 0.53; CI, 0.42-0.68). Elective surgery patients had a significant decrease in length of hospital stay.

  • Studies with higher methodological scores (>8) had a significant decrease in hospital stay,

  • Effect of immunonutrition on critically ill patients—immunonutrition was associated with a reduction in length of hospital stay and decrease mortality.

  • Immunonutrition had fewer days on mechanical ventilator.

Author Conclusion:

Did not find a statistically significant benefit of immunonutrition on mortality, decrease in number of patients with infectious complications and shorter length of hospital stay. However, the heterogeneity of the results across the studies was significant which decreases the strength of the analysis.   Subgroup analysis was hypothesis generating not confirming.

Trend toward higher mortality in critical ill and immunostimulation in elective surgery patients reduced mortality and infections.

Immunonutrition may decrease infectious complications in elective surgery patients and may be harmful in critically ill patients.

Funding Source:
Reviewer Comments:

Good study, agree with authors conclusions.

Quality Criteria Checklist: Review Articles
Relevance Questions
  1. Will the answer if true, have a direct bearing on the health of patients? N/A
  2. Is the outcome or topic something that patients/clients/population groups would care about? N/A
  3. Is the problem addressed in the review one that is relevant to dietetics practice? N/A
  4. Will the information, if true, require a change in practice? N/A
Validity Questions
  1. Was the question for the review clearly focused and appropriate? N/A
  2. Was the search strategy used to locate relevant studies comprehensive? Were the databases searched and the search termsused described? N/A
  3. Were explicit methods used to select studies to include in the review? Were inclusion/exclusion criteria specified andappropriate? Wereselectionmethods unbiased? N/A
  4. Was there an appraisal of the quality and validity of studies included in the review? Were appraisal methodsspecified,appropriate, andreproducible? N/A
  5. Were specific treatments/interventions/exposures described? Were treatments similar enough to be combined? N/A
  6. Was the outcome of interest clearly indicated? Were other potential harms and benefits considered? N/A
  7. Were processes for data abstraction, synthesis, and analysis described? Were they applied consistently acrossstudies and groups? Was thereappropriate use of qualitative and/or quantitative synthesis? Was variation in findings among studies analyzed? Were heterogeneity issued considered? If data from studies were aggregated for meta-analysis, was the procedure described? N/A
  8. Are the results clearly presented in narrative and/or quantitative terms? If summary statistics are used, are levels ofsignificance and/or confidence intervals included? N/A
  9. Are conclusions supported by results with biases and limitations taken into consideration? Are limitations ofthe review identified anddiscussed? N/A
  10. Was bias due to the review's funding or sponsorship unlikely? N/A