CI: Immune-Modulating Enteral Nutrition (2006)

Study Design:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To systematically review the effects of enteral nutrition with pharmaconutrient-enriched diets in critically ill patients and to establish recommendations for their use.

Focus was to answer the following question: “Compared to enteral nutrition with standard diets, has the use of diets enriched with pharmaconutrients significantly improved the outcome of critically ill patients?”


Inclusion Criteria:

Randomized clinical trials of critically ill patients treated with enteral nutrition comparing diets enriched with pharmaconutrients vs. standard diets.

Studies measured clinical outcomes such as mortality or infectious complications.

Studies published from 1966-2000, available on the Cochrane Central Database, MEDLINE, and EMBASE databases, as well as references of the original articles and abstracts proceedings of scientific meetings.

Exclusion Criteria:

Studies comparing immune enhancing diets (IED) with oral diets or parenteral nutrition.

Unpublished studies.

Description of Study Protocol:


  1. The clinical group elaborated a document containing the theoretical basis for the application of immunonutrition in ICU patients and the objectives of the systematic review. Type of patients, nutritional interventions, and outcome variables were defined by consensus. 
  2. The methodological group independently defined the search strategy, carried out the statistical analysis, performed the systematic review, and presented a document with their results.
  3. The document was discussed with the clinical group and conflicting results were identified. 
  4. A definitive methodological document was created following resolution of the problems identified during the discussion.       
  5. The clinical group analyzed the clinical implications of the review and came to consensus on a set of recommendations about the use of immunonutrition in critically ill patients.  The methodological group was present during the clinical consensus meeting but did not participate in discussions.


Studies were classified into four subgroups according to the patient’s primary diagnosis:  surgical, trauma, burned, or medical.

Data Extraction

A group of experts in methodology (from the Ibero-American Cochrane Center, “methodological group”) performed data extraction and statistical processes.  A global analysis of the studies was done as well as a separate study for each subgroup.  Results of the meta-analysis were discussed with a group of clinicians experienced in the nutritional support of ICU patients (from the Nutritional and Metabolic Working Group of the Spanish Society of Intensive Care Medicine and Coronary Units, “clinical group”) to come to an agreement and make recommendations for the use of pharmaconutrient-enriched diets in critically ill patients.

Data were extracted with a structured form in duplicate and checked for accuracy independently.

Statistical Analysis

The methodological quality of the selected trials were assessed using the Jadad’s scale.  The quality score was used to explain the heterogeneity of the results and to establish the level of evidence.

Primary outcomes were analyzed by intention-to-treat.  Data was combined from individual studies and treatment effects were calculated using the fixed effects meta-analysis method.  Overall odds ratio and 95% confidence intervals were calculated with the Peto’s method.  Continuous variables were analyzed with the pooled differences in means test.  Heterogeneity was assessed with the Q-test.  Funnel plots assessed publication bias and a statistical test of funnel plot asymmetry was performed.

Data Collection Summary:

Dependent Variables

  • nosocomial infection rate

  • days on mechanical ventilation

  • ICU- and hospital length of stay (LOS)

  • in-hospital mortality

  • adult respiratory distress syndrome incidence (ARDS)

  • multiple organ dysfunction syndrome (MODS)

  • cost

Independent Variables

Use of IED Enteral Nutrition (EN)

Control Variables

Use of standard EN

Description of Actual Data Sample:

Initial N:

Search strategy retrieved 684 references. 267 articles were independently reviewed, however, only 35 were identified as relevant randomized studies.  Of those, 7 papers contained secondary data from one primary study, only the primary study was included in analyses; and 2 studies were excluded for having unclearly identified control and study groups.  

Attrition (final N):

26 studies were included in the meta-analysis.

Compositions of Study Diets:

Commercial diets were used as the independent variable in 20 studies.

Specially-prepared diets were used as the independent variable in 6 studies.

Glutamine-enriched diets were used as the independent variable in 2 studies.

Fish oil-enriched diets were used as the independent variable in 2 studies.

Exclusive arginine-enrichment was used as the independent variable in 1 study

A modular formula enriched with arginine and n-3 fatty acids diets was used as the independent variable in 1 study.

Control diets were isocaloric in 19 studies.

Control diets were isonitrogenous in 17 studies.

Control diets were neither isocaloric nor isonitrogenous in 5 studies.

Control diets were isocaloric but not isonitrogenous in 4 studies. 

Patient Population

9 studies included only surgical patients.

7 studies included trauma patients.

2 studies included only burn patients.

8 studies included a mixed population.


Meta-analysis was done for the Nutritional and Metabolic Working Group of the Spanish Society of Intensive Care Medicine and Coronary Units (SEMICYUC), Spain

Summary of Results:

Outcomes Significance Odds Ratio Confidence Interval p Value number of studies
Infectious complication rate No significant effect of IED




Most studies did not present the overall ratio of infected patients.
Wound infection Significant effect of IED 0.46 0.30-0.69 p=0.003 5 describe incidence of patients infected; 10 others describe the wound infection
Intraabdominal absess Significant effect of IED 0.26 0.12-0.58 p=0.0005  6
Nosocomial pneumonia Significant effect of IED 0.54 0.35-0.84 p=0.007  11
Bacteremia Significant effect of IED 0.45 0.29-0.69 p=0.0002 9
Urinary tract infection No significant effect of IED 0.66 0.43-1.0 p=0.05  10
Sepsis No significant effect of IED 0.45 0.14-1.45 p=0.18  5

ARDS- / 

*MODS incidence

No significant effect of IED (ARDS) / *Significant effect of IED (*MODS) *0.21 *0.09-0.52 *p=0.0007  1 (ARDS)/ *2 (*MODS)
Mechanical ventilation duration Significant effect of IED, reduced 2.25 days  


-0.5,-3.9 p=0.009  7
ICU- / hospital LOS Significant effect of IED: reduced by 1.6 / 3.4 days   


-1.2,-1.9 / 2.7-4 p=0.0001  / p=0.0001 


Note:  aggregate results had heterogeneity in both measures.






3 studies calculated added cost of nutritional intervention to hospital- or ICU costs:  2 showed reductions; on showed no difference

In-hospital Mortality Overall

Subgroup surgical



mixed patient

No significant effect of IED (overall- and subgroup analyses)












18 (overall)

Author Conclusion:

Considering the beneficial effects and the absence of detrimental ones, the use of diets enriched with pharmaconutrients could be recommended in ICU patients requiring enteral feeding. Nevertheless, more investigation is needed in this field in order to find the more appropriate population of patients that can be helped with this nutritional therapy.

Funding Source:
Novartis Consumer Health (Spain)
Pharmaceutical/Dietary Supplement Company:
Reviewer Comments:

The information is organized in table format for easy review.

The meta-analysis identifies that future studies should select more-homogeneous populations to assess the effect of IED in critically ill patients.  Critical illness should be clearly defined by primary diagnosis and with severity scores such as APACHE II or SAPS.

Additionally, more studies must be done to assess the cost/benefit of IED diets.  

Quality Criteria Checklist: Review Articles
Relevance Questions
  1. Will the answer if true, have a direct bearing on the health of patients? Yes
  2. Is the outcome or topic something that patients/clients/population groups would care about? Yes
  3. Is the problem addressed in the review one that is relevant to dietetics practice? Yes
  4. Will the information, if true, require a change in practice? Yes
Validity Questions
  1. Was the question for the review clearly focused and appropriate? Yes
  2. Was the search strategy used to locate relevant studies comprehensive? Were the databases searched and the search termsused described? Yes
  3. Were explicit methods used to select studies to include in the review? Were inclusion/exclusion criteria specified andappropriate? Wereselectionmethods unbiased? Yes
  4. Was there an appraisal of the quality and validity of studies included in the review? Were appraisal methodsspecified,appropriate, andreproducible? Yes
  5. Were specific treatments/interventions/exposures described? Were treatments similar enough to be combined? Yes
  6. Was the outcome of interest clearly indicated? Were other potential harms and benefits considered? Yes
  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? Yes
  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? Yes
  9. Are conclusions supported by results with biases and limitations taken into consideration? Are limitations ofthe review identified anddiscussed? Yes
  10. Was bias due to the review's funding or sponsorship unlikely? Yes