CI: Initiation of Enteral Nutrition (2012)

Study Design:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To assess the effects of enteral nutrition (EN) started immediately after injury on intestinal permeability and on the severity of multiple organ failure (MOF), as compared to starting EN one to two days after admission.
Inclusion Criteria:
  • Multiple trauma: Defined as involving at least three different organ systems in different parts of the body with at least one life-threatening organ injury
  • Injury Severity Score (ISS) of greater than 25 and a Glasgow Coma Score of greater than 12
  • Admitted in shock but stabilized under six hours of admission with a shock index of  less than one and systolic blood pressure more than 100mmHg.
Exclusion Criteria:
No specifics given. 
Description of Study Protocol:

Consecutive admissions to ICU involving muliply injured patients, in shock and stabilized in six hours. 


Laboratory technician conducting mannitol and lactulose assays was blinded to group assignment.

  • Patients were randomly assigned by closed envelopes at the beginning of the study 
    • Group A patients were placed on immediate intragastric tube feeding of Jevity at 20ml per hour between six and 24 hours after admission. Volume was adjusted related to GI tolerance, assessed by gastric residuals.
    • Group B patients received TPN the first 24 hours, then started on enteral nutrition (EN) after 24 hours.
  • The goal of EN or TPN was to meet 50% of calculated nutritional needs within the first 24 hours of EN, 75% the next day and 100% within 72 hours of admission 
    • Aim of feeding was to reach a target value of 0.2 to 0.3g N per kg body weight per day and on average 25 to 35 non-protein kcal per kg body weight per day within 72 hours
  • Both groups received TPN to meet nutritional needs
  • Both groups received prokinetic agent to manage gastric residuals
  • Five normal volunteers completed the lactulose and mannitol assay on Day 4 for determinaiton of normal reference values.

Statistical Analysis

  • Data are presented as median and interquartile range or as means ± SD
  • Student's T-test with analysis of variance or the Mann-Whitney U test was used to make comparisons between the unpaired data
  • Wilcoxon rank sum test was used to determine differenced between paired data
  • Pearson's test was used for the correlation analysis
  • P<0.05 was considered statistically significant.
Data Collection Summary:

Timing of Measurements

  • Gut permeability was determined on days two and four after admission
  • Multiple organ failure (MOF) scores were determined daily
  • Organ system function was determined by serum aspartate, alanineaminotransferease, total bilirubin, creatinine, leukocyte and platelet counts and respiratory gases in arterial blood from day of admission until day 14, or until the last day in the ICU.

Dependent Variables

  • Gut permeability: Determined by measuring the ratio of lactulose and mannitol in the urine
  • MOF: Defined as failure as more than two organs occurring during the patient's ICU stay
    • Early: Days one to three
    • Late: Days four to 14 or until the day of discharge from ICU
    • Score rated organ failure (not present, moderate or severe) in six organ systems (respiratory, circulation, kidney, liver, blood and GI tract).

Independent Variables

  • Immediate EN
  • Enteral nutrition initiated greater than 24 hours after admission.
Description of Actual Data Sample:
Initial N: 36
Attrition (final N): 28
  • Group A
    • N=14 (all men)
    • Three patients withdrawn
  • Group B
    • N=14 (10 men; 4 female)
    • Five withdrawn
  • Withdrawals due to:
    • Incomplete measurements: N=6 [improperly processed samples (N=2), early discharge from ICU (N=1), intravenous mannitol (N=2), lactulose as laxative (N=1)]
    • Intolerance to enteral feeding and placed on TPN: N=1
    • Enteral feeding initiated earlier than stated protocol: N=1


  • Group A: 38.4±15.6
  • Group B: 44.7±15.9


Not described.

Other Relevant Demographics

  • Injury Severity Score
    • Group A: 31.4±11.7
    • Group B: 35.7±7.7
  • Blood transfusion on day one (ml)
    • Group A: 1,435±1,715
    • Group B: 2,765±2,510
  • Shock index
    • Group A: 1.5±0.5
    • Group B: 1.3±0.4
  • APACHE II on admission
    • Group A: 11.7±5.4
    • Group B: 11.2±4.4
  • Mechanical ventilation [days, median (interquartile range 25 to 75%)]
    • Group A: 8.0 (9.3 to 17.5)
    • Group B: 11.9 (6 to 17.7)
  • Days in ICU [median (interquartile range 25 to 75%)]
    • Group A: 11 (10.5 to 24.7)
    • Group B: 14 (7.2 to 20).


Not described. 


University Clinical Centre, Ljubljana, Slovenia.




Summary of Results:
  • The average MOF scores showed significant differences between the groups concerning the onset of late MOF (P<0.002). Time of initiation of EN correlated with late MOF scores (r=0.46) and hepatic failure (r=0.42).  The longer the time between admission and starting enteral feeding the greater the MOF scores.
  • Median L/M ratio for group A and group B was 0.024 and 0.045, respectively (P<0.02). The difference in L/M ratio between group B on day two and normal volunteers was statistically significant (P<0.05). All 28 patients the L/M ratio on day two correlated with late MOF scores (r=0.44) and with liver failure (r=0.38), with the L/M ratio on day four correlated with ISS (r=0.38) and with the time of initiation of enteral nutrition after injury (r = 0.55).
  • No influences on length of stay in ICU or length of time on mechanical ventilation.

 Other Findings

  • Median time of initiation of enteral feedings in group A was 4.4 (3 to 5.7) hours. Median time of initiation of enteral feedings in group B was 36.5 (24.5 to 47) hours.
  • Mean volume of enteral feeding delivered on day four in group A was 1340±473ml vs. 703±701ml in group B (P=0.009)
  • Mean percentage of enteral nutrition received per day by the end of week 1 was 80.5±16.3% in group A vs. 60.9±25.6% in group B (P=0.025).
Author Conclusion:
  • On average, the patients in group B had increased gut permeability by the lactulose/mannitol assay compared to group A and normal volunteers
  • Tube feeding intolerance problems in severely injured patients may be avoided by immediate initiation of EN.
Funding Source:
Government: National Institute for Chemistry (Slovenia)
University/Hospital: University Clinical Centre, Lubljana, Slovenia
Reviewer Comments:
  • Small sample with no sample size calculation
  • Randomization method not described
  • Groups were not balanced with gender
  • Laboratory technician for lactolose/mannitol assay was blinded to groups
  • For MOF scores calculated on 23 to 25 subjects. Unsure why this number differs from the reported number in the final analysis.
  • For group B, timing of enteral feeding initiation after 24 hours was vague
  • Article indirectly supports reduction in cost  with early enteral feeding and to a lesser degree morbidity and mortality associated with MOF.
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) No
  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? No
  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? No
  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? N/A
  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? ???
  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? ???
  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? ???
  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)? No
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? No
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
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? No
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? Yes