CI: Immune-Modulating Enteral Nutrition (2006)

Study Design:
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Quality Rating:
Research Purpose:

To evaluate the effects of a high-protein formula enriched with arginine, fiber, and antioxidants compared with a standard high-protein formula in early enteral nutrition in critically ill patients.

Inclusion Criteria:

Patient admitted to any 1 of 15 participating ICUs following an acute event, and predicted to need enteral nutrition support for >7d.

Exclusion Criteria:

Age <18y, APACHE II score <8, MOD score >5, pregnancy, expected survival <24h, previous cardiopulmonary resuscitation, diabetes, chronic gastrointestinal disease, renal failure (serum creatinine >220 mmol/L or higher or dialysis), liver failure (serum bilirubin of >43 mmol/L or previous history of chronic liver disease), cancer, HIV infection, or previous use of corticosteroids, salicilates, anti-inflammatory drugs, or immunosuppressive drugs.

Description of Study Protocol:


Gastric or jejunal enteral feedings were delivered at full strength through 24-hour infusions. Patients were encouraged to maintain a semirecumbent position (30o).  Feedings were initiated at 42mL/h for the first 24h, thereafter increased by 20mL/h every 12h until caloric goals were achieved.  Containers and delivery systems were changed after 24h of use. 

Caloric requirements were based as 25 kcal/kg/d, goals were to be achieved with the first 72h of enteral nutrition.  Planned and actual caloric intakes were documented at days 3 and 7 of treatment.  Patients were followed prospectively until hospital discharge, and a follow-up survey was conducted 6 months later to check mortality. 

Blinding used (if applicable)


Intervention (if applicable)

The control diet (Nutrison Protein Plus, Nutricia Spain S.A.) and the immune-enhanced diet, IED (Stresson Multifibre, Nutricia Spain S.A.) both contained intact proteins and were supplemented with selenium.  The formulas had the following nutrient comparisons (control : IED):  grams of protein/L (62.5 : 75), non-protein calories to nitrogen ratio (102:1 : 83:1), percent MCT (0 : 40), grams of fiber/L (0 : 8.9) and omega-3:omega-6 ratios (1:5 : 1:3.45).  Additionally, the IED was enriched in arginine (11.8%) and vitamins A, C, and E. 

Statistical Analysis

Statistical analysis was conducted for 2 sets of data--data from randomized patients that met the inclusion and exclusion criteria (intent-to-treat analysis) and data from the subset of patients who were fed enterally for >2d.  Continuous data were assessed for normality, and the tests used were a 2-tailed Student test for normal data and a Mann-Whitney test for non-normal distributions.  A 2-tailed X2 test was applied for proportions.  Relative risk was calculated for mortality and incidence density infection rates.  Survival was assessed with the Kaplan-Meyer survival curves.  Quantitative data are expressed in median and interquartile range, if not otherwise stated. 

Data Collection Summary:

Timing of Measurements

The following were recorded: age, sex, weight, primary diagnosis, group (medical, surgical, or trauma), APACHE II score, MODS, need for mechanical ventilation, and the presence of sepsis or septic shock.

Time of first feeding, type and caliber of feeding tube, access route, and duration of use of the access route were documented.

Gastrointestinal complications including abdominal distention, increased gastric residuals, vomiting, diet regurgitation, diarrhea, constipation were recorded prospectively. 

Patients were observed for symptoms of infections (i.e. pneumonia, bacteremia, intra-abdominal infection, urinary tract infections, contaminated wounds, or catheter-related sepsis.) 

Dependent Variables

  • ICU mortality
  • in-hospital mortality
  • 6-month mortality
  • hospital LOS
  • infection incidence density rates (all infections, nosocomial pneumonia, bacteremia, catheter-related sepsis, surgical infections, UTI)

Independent Variables

Enteral nutrition with immune enhanced diet (IED) formula enriched with protein, MCT, ratio of omega-3:omega-6 fatty acids, fiber, vitamin A, vitamin C, vitamin E, and selenium 

Control Variables

Enteral nutrition with control formula enriched with protein and selenium 

Description of Actual Data Sample:

Initial N:

220 patients were eligible for analysis (122 control, 98 IED). There were no significant differences in baseline characteristics between the 2 groups (control:IED) including average age (58 : 51), sex (30 : 31 % female), primary diagnosis, presence of sepsis on admission, need for mechanical ventilation, average APACHE II scores (16 : 17), hospital mortality rates (29 : 25), energy requirements (1875 : 1750 kcal/d), or planned caloric intake at days 3 (1500 : 1470) and 7 (1440 : 1440).  Patients receiving the control formula actually received significantly more calories at day 7 (1750 vs. 1538, p < 0.04).

190 patients (85 control, 105 IED) were fed enterally for >2d.  No differences were found in the demographic, enteral nutrition –baseline, or -withdrawl characteristics between the two groups except that patients receiving the control formula received significantly more calories at day 7 (1793 vs. 1616, p < 0.01).

Location:  15 ICU centers in Spain 

Summary of Results:

The following results were observed in the 190 patients who received enteral nutrition for >2d:


Treatment Group

Measures and confidence intervals

Control group

Measures and confidence intervals

Statistical Significance of Group Difference

ICU Mortality (%)




In-Hospital Mortality (%)




6-month Mortality (%)

23.8 32.9 p=.1

ICU LOS (days)

17 14 p=.02

Hospital LOS (days)

33 29 p=.3

Overall infection incidence density rate

38.8 37.0 p=.8

nosocomial pneumonia incidence density rate

33.4 25.3 p=.3

bacteremia incidence density rate

7.1 7.1 p=1.0

catheter related sepsis incidence density rate

0.4 5.8 p<=.001

surgical infection incidence density rate

1.98 1.95 p=1.0

UTI incidence density rate

7.1 3.2 p=.1


Author Conclusion:

Critically ill patients fed a diet enriched with arginine, MCT lipids, fiber, and high doses of vitamins A, C, and E had a significantly lower catheter-related sepsis rate than patients in the control group. There was no differences in mortality or ICU- and hospital- length of stay.  The subgroup of patients fed the study diet for >2d showed a trend toward decreased mortality.

Funding Source:
Nutricia (Spain)
Food Company:
University/Hospital: Fundacion Jimenez Diaz, HosPital Severo Ochoa, Hospital Universitario de Getaf (Spain)
Reviewer Comments:

Data sample gender was approximately 30% female in both groups.

The data sample was less sick and had lower APACHE II scores than expected as a result of excluding patients with a MODS score >5.  Enteral feeding was initiated within 40h of admit.  The study supports the usefulness of enteral feeding in this level of critically ill patients and could confirm the hypothesis that early administration can ameliorate the immunological and nutritional state and improve the prognosis of these patients.

Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? ???
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? N/A
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? ???