CI: Initiation of Enteral Nutrition (2012)


Khalid I, Doshi P, DiGiovine B. Early enteral nutrition and outcomes of critically ill patients treated with vasopressors and mechanical ventilation. Am J Crit Care. 2010 May; 19 (3): 261-268. Erratum in: Am J Crit Care. 2010 Nov; 19 (6): 488. PMID: 20436064.

PubMed ID: 20436064
Study Design:
Retrospective Cohort Study
B - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To determine the effect of early enteral feeding on the outcome of hemodynamically-unstable critically-ill medical patients.

Inclusion Criteria:

 Patients were included if:

  • Admitted to ICU and received mechanical ventilation for longer than two days
  • In unstable hemodynamic condition (considered if they were given the vasopressor agents norepinephrine, epinephrine, dopamine or phenylephrine during the first two days of ventilatory support)
  • Lived longer than two days once mechanical ventilation was initiated
  • Did not have an absolute or relative contraindication to enteral nutrition at the time of admission
  • Did not receive TPN before treatment with mechanical ventilation.
Exclusion Criteria:

 Patients were excluded if:

  • Admitted to ICU but died or were extubated within two days of the start of mechanical ventilation
  • Not in unstable hemodynamic condition (considered if they were not given the vasopressor agents norepinephrine, epinephrine, dopamine or phenylephrine during the first two days of ventilatory support)
  • Had an absolute or relative contraindication to enteral nutrition at the time of admission (gastrointestinal obstruction or bleeding, intestinal ileus, gastroparesis, acute pancreatitis, peritonitis, ischemic colitis or esophageal rupture)
  • Received TPN before treatment with mechanical ventilation.
Description of Study Protocol:


Data were obtained from a large, multi-institutional critical care patient data set: Project Impact Critical Care Data System.


  • Coordinators at each of the participating sites collected the data prospectively from patients' charts for the Project Impact data set
  • Baseline information collected on each patient included age, sex, race, admitting diagnosis, medications received, MPM-0 score, SAPS II and APACHE II score
  • Data for this study were requested on all non-surgical patients admitted to an ICU who received mechanical ventilation during their ICU stay and were hemodynamically-unstable when mechanical ventilation was started
    • These data were analyzed retrospectively for ICU and hospital mortality
    • The cohort was divided into two groups and analyzed according to when EN was first started: Early EN included patients who were started on EN within 48 hours of the start of mechanical ventilation, while the remainder of the patients were considered late EN
    • Analyses were also done on two subgroups: Patients given two or more vasopressor agents and patients treated with vasopressors for more than two days after the start of intubation. 

Blinding Used




Statistical Analysis

  • Baseline characteristics of the two groups were compared using unpaired T-tests, the Kruskal-Wallis test and the chi-squared test
  • Kaplan-Meier survival analysis was used to evaluate the impact of early EN on mortality and the time from mechanical ventilation to death was compared using a log-rank test
  • Logistic regression was used to evaluate the effect of early EN on ICU and hospital mortality after adjustments were made for confounders
  • Cox proportional hazard analyses were used to determine the effect of EN on risk of death.
Data Collection Summary:

Timing of Measurements

Data were collected prospectively from patients' charts by coordinators at the participating sites but analyzed retrospectively.  Data analyzed were acquired in January 2003. 

Dependent Variables

Primary outcomes:

  • ICU mortality
  • Hospital mortality

Secondary outcomes:

  • occurrence of VAP
  • ventilator -free days
  • vasopressor -free days

Independent Variables

  • Early EN - patients who were started on EN within 48 hours of the start of mechanical ventilation
  • Late EN - all other patients in the cohort.

Control Variables

  • Logistic regressions to evaluate the effect of early EN on VAP included the use of drugs that may have confounded analyses (histamine2 blockers, proton-pump inhibitors, narcotics, and paralytic agents). 
  • To control for residual bias, propensity scores were used to match pairs of patients from each group. After matching was completed, this data set was assessed using a matched t test, conditional logistic regression, Kaplan-Meier survival analyses as well as Cox proportional hazard methods. 
Description of Actual Data Sample:
  • Initial N: 707 patients in the Early EN Group (384 male, 323 female) and 467 patients in the Late EN Group (260 male, 207 female; P=0.65 for gender).
  • Attrition (final N): None: Same as initial N.
  • Age: Mean age of patients in the Early EN Group was 64.8 years, while mean age of patients in the Late EN Group was 62.8 years (P<0.04).


  • The Early EN Group was:
    • 82.0% white
    • 12.6% African-American
    • 2.7% Hispanic
    • 2.1% other
    • 0.6% unknown.
  • The Late EN Group was:
    • 77.1% white
    • 17.6% African-American
    • 2.6% Hispanic
    • 1.5% other
    • 1.7% unknown.
  • P=0.10 for race.

Other Relevant Demographics

  • The reason for ICU admission was significantly different between groups:
    • Respiratory problem: 383 patients in the Early EN Group; 171 in the Late EN Group
    • Sepsis: 98 patients in the Early EN Group; 79 in the Late EN Group
    • Cardiac problem: 97 patients in the Early EN Group; 125 in the Late EN Group
    • Central nervous system disorder: 66 patients in the Early EN Group; 32 in the Late EN Group
    • Others: 63 patients in the Early EN Group, 60 in the Late EN Group.
  • P<0.001 for all reasons.


  • APACHE II score: 23 for the Early EN Group; 24.6 for the Late EN Group (P<0.002)
  • MPM-0 score: 0.39 for the Early EN Group; 0.42 for the Late EN Group (P=0.07)
  • SAPS II score: 52 for the Early EN Group; 55.3 for the Late EN Group (P<0.001).


Not specified: Data from sites participating in the Project Impact Critical Care Data System through the Society of Critical Care Medicine. 

Summary of Results:

Key Findings

  • Early EN was consistently associated with a lower risk of hospital mortality, regardless of severity of illness score used
  • After correcting for confounders, the Cox proportional hazards model found early EN was associated with a 30% to 35% decreased risk of death
  • In patients matched for propensity score, patients in the Early EN Group had significantly lower hospital mortality than did the Late EN Group (34.1% vs. 42.7%, P=0.01)
  • The Cox PH model in the patients matched for propensity score found early EN was associated with a 34% decreased risk of death (OR, 0.66; 95% CI, 0.49 to 0.89; P=0.006)
  • The benefit of early EN is more evident in the sickest patients, those receiving multiple vasopressors (OR, 0.36; 95% CI, 0.15 to 0.85) and for more than two days (OR, 0.59; 95% CI, 0.39 to 0.90). These results remained about the same when outcomes were assessed at 28 days.


Early EN Group
Measures and confidence intervals

Late EN Group
Measures and confidence intervals

Statistical Significance of Group Difference

ICU Mortality, Number of Patients (percentage)

159 (22.5)

132 (28.3)


Hospital Mortality, Number of Patients (percentage)

 239 (33.8)

 205 (43.9)


Hospital Mortality, Number of Patients (percentage) After Matching for Propensity Score

 121 (33.9)

 152 (42.6)


ICU LOS (days)
27 (12.2)
25.9 (12.0)

Author Conclusion:
  • Early EN is associated with a reduction in the mortality of critically-ill patients receiving mechanical ventilation who are in an unstable hemodynamic condition, as indicated by the use of vasopressors
  • The beneficial effect of early EN is more evident in patients treated with multiple vasopressors
  • In addition, no evidence of harm due to early EN was found in this study population. 
Funding Source:
Other: Not specified.
Reviewer Comments:

 The authors list several limitations to this study:

  • The study does not take into account patients' total caloric intake, rate of advancement and disruptions in feedings
  • Confounding by indication: The decision to provide EN was not made randomly; EN may be a marker of a less ill patient
  • If a physician is more likely to initiate early EN, he may also be more likely to follow other measures to improve outcomes
  • Unmeasured variables could not be controlled, which may have provided residual confounding.

EN = Enteral nutrition
ICU = Intensive care unit
LOS = Length of stay
APACHE II = Acute Physiology and Chronic Health Evaluation II
Cox PH = Cox proportional hazard
MPM-0 = Mortality Prediction Model at time zero
SAPS II = Simplified Acute Physiology Score II
VAP = Ventilator-associated pneumonia.

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? Yes
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) N/A
  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? Yes
  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? No
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  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.) No
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? No
  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? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  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? 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)? Yes
  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? Yes