CI: Immune-Modulating Enteral Nutrition (2006)


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

Worksheet created prior to Spring 2004 using earlier ADA research analysis template.
Study Design:
Meta-analysis or Systematic Review
M - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To perform a meta-analysis addressing whether enteral nutrition with immune-enhancing feeds benefits critically ill patients after trauma, sepsis, or major surgery.
Inclusion Criteria:

·   Medline search (1967-1998)

·   Original articles

·   Published in English

·   Search terms: human, enteral nutrition, arginine, nucleotides, omega-3 fatty acids, immunonutrition, Impact, Immun-Aid

·   Published and unpublished articles from both manufacturers

·   Target population consisted of critically ill patients requiring enteral nutrition via a tube

·   Only trials with institutional approval and informed consent were included

·   Randomized trials that compared critically ill patients who received enteral  nutrition with a feed enriched with arginine with or without glutamine, nucleotides, and omega-3 fatty acids with pt receiving a standard enteral feed preparation and outcome measures of mortality, infection rate, days of mechanical ventilation,  ICU length of stay, hospital length of stay, and days with diarrhea.

Exclusion Criteria:

·   Trials that do not have experimental and control groups matched in the beginning

·   Trials that patients overlap into larger studies

Description of Study Protocol:

Descriptive and outcome data were extracted independently from the papers by the same two reviewers.  Abstraction differences were resolved by consensus between the two reviewers.  Access to the original data sets (4-6) allowed determination of whether the primary diagnosis was medical, surgical, or trauma based and identification of individual patients who died.

Data Collection Summary:

Outcome measures:

·   Mortality

·   Infection

·   Ventilator days

·   ICU stay

·   Hospital stay

·   Diarrhea days

·   Calorie intake

·   Nitrogen intake


Meta-analysis performed on an intent-to-treat basis.


Infection and mortality were treated as binary variables. 


Meta-analysis results were expressed in terms of a relative risk (RR) for the treatment group vs. control group, such that RR < 1 favored treatment group and RR > 1 favored control group.


Ventilator days, ICU LOS, hospital LOS, diarrhea days, calorie intake, and nitrogen intake were treated as continuous variables. 


The outcome measure was the number of days for the treatment group minus the number of days for the control group, such that a negative number favored the treatment group and a positive number favored the control group.


Subgroup analyses were performed on each of the medical, surgical, and trauma groups, for each outcome variable. 


Standard heterogeneity tests were conducted, and funnel plots of the primary outcome variables were created.


To correct for confounding effects of differences in overall mortality or in early death rate when overall mortality was the same on a comparison of time-dependent variables such as number of infections, ventilator days, and length of stay, the meta-analysis was repeated censored for no survivors.

Description of Actual Data Sample:


· 15 trials met the inclusion criteria, one excluded due to significant differences in exp and control group at the start of trial, 2 excluded because pt were included in larger trials leaving 12 studies.

· 1557 pt enrolled, of which 1482 were included in an intent-to-treat analysis


Summary of Results:

· Interobserver correlation co-efficient for the quality assessment by two reviewers was r2 = 0.85

No overall effect of feeding on mortality and no heterogeneity between the studies.

Immunonutrition has significant reduction in relative risk (RR) of acquiring infection in overall group and surgical subgroup, no heterogeneity between studies.

Ventilator days—significant reduction in overall and trauma subgroup and remained so after censoring for mortality.  No heterogeneity between trials.

ICU LOS—no significant reduction due to treatment.

Hospital LOS—no heterogeneity between trials.  Significantly reduced in overall group, surgical subgroup, and medical subgroup.  Difference still significant after censoring for mortality.

Diarrhea days—No increase in side effects of feeding were reported in pt receiving immunonutrition.

Calories—No significant difference between groups after censoring for mortality.

Nitrogen-Treatment group received 0.04g/kg/day more N than control group.  For the subgroup of trauma pts, the treatment group received 0.03 g/kg/day more than control group.  These results remained significant when censored for mortality.  There was no sig differences in N intake for either the surgical pt or the medical pt.

Acute Physiology and Chronic Health II Score—No significant differences between treatment and control groups overall.  However, in the subgroup of medical pt, the APACHE II score was significantly higher by 1.2 points in the treatment groups. 


Author Conclusion:

Trials varied in size, quality, and pt case mix, but all showed some positive effect on immunonutrition, which was maintained in the meta-analyses and could not be explained by differences in mortality or N intake between groups.  There was no evidence of any detrimental effect of immunonutrition.  Results of this analysis do not support that immune-enhancing feeds be reserved for the sickest pt.  The benefit was most marked in the surgical group.

Funding Source:
Reviewer Comments:

Tests for heterogeneity were applied and duplicate analysis was avoided.

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