CI: Enteral Nutrition Energy Delivery (2012)


Arabi YM, Tamim HM, Dhar GS, Al-Dawood A, Al-Sultan M, Sakkijha MH, Kahoul SH, Brits R. Permissive underfeeding and intensive insulin therapy in critically ill patients: A randomized controlled trial. Am J Clin Nutr. 2011 Mar; 93 (3): 569-577. Epub 2011 Jan 26. PMID: 21270385.

PubMed ID: 21270385
Study Design:
Randomized Controlled Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
  • Examine the effect of permissive underfeeding compared with target calorie intake on outcomes of critically ill patients
  • Examine the effect of intensive insulin therapy with conventional insulin therapy on outcomes of critically ill patients.
Inclusion Criteria:
  • More than 18 years old
  • Blood glucose >110mg/dL
  • Enteral nutrition (tube feeding)
  • At least 48-hour expected length of stay in medical-surgical intensive care unit.
Exclusion Criteria:
  • Type 1 diabetes
  • Diabetic ketoacidosis
  • Hypoglycemia
  • Brain death
  • Do-not-resuscitate status
  • Terminal illness
  • Post cardiac arrest
  • Seizures within the past six months
  • Pregnancy
  • Liver transplant
  • Burns
  • Readmission to the intensive care unit within the same hospitalization
  • Oral feeding
  • Total parenteral nutrition
  • Enrollment in a competing trial.
Description of Study Protocol:


Medical-surgical intensive care unit patients meeting inclusion criteria between April 2006 and January 2008.


RCT; Patients were randomly assigned by using concealed envelopes to one of four groups. Stratified randomization was used for diabetic and non-diabetic patients.

Blinding used

This study was not blinded.


  • Permissive underfeeding (goal: 60 to 70 percent of estimated calorie requirement)
  • Target feeding (goal: 90 to 100 percent of estimated calorie requirement)
  • Intensive insulin therapy (goal: blood glucose concentration maintained at 80 to 110mg/dL)
  • Conventional insulin therapy (goal: blood glucose concentration maintained at 180 to 200mg/dL).

Statistical Analysis

  • Data were analyzed using an intent-to-treat principle
  • T-test was used for continuous variables and chi-square test for categorical variables
  • Mortality data were assessed using relative risk and confidence intervals. Rates were assessed using z approximation, and Kaplan-Meier survival curves using a log-rank test.
  • Power of 0.8 and α=0.05 predicted a need for 120 participants in each of the two arms.
Data Collection Summary:

Timing of Measurements

 Calculated daily:

  • Mean blood glucose
  • Total insulin dose
  • Total calorie intake
  • Daily protein intake.

Data collected at baseline included:

  • Age
  • Sex
  • Anthropometrics (height, weight, body mass index)
  • Diabetes
  • Inclusion blood glucose
  • Admission category (non-operative or post-operative)
  • Traumatic brain injury
  • APACHE II score
  • SOFA score, day one
  • Mechanical ventilation
  • Vasopressor 
  • Sepsis
  • Creatinine
  • Bilirubin
  • Platelets
  • INR
  • PaO2:FiO2
  • GCS
  • Time to randomization.

Dependent Variables

  • 28-day all-cause mortality
  • ICU, hospital, and 180-day mortality
  • ICU and hospital length of stay
  • Mechanical ventilation duration.

Independent Variables

  • Calorie intake (60 to 70 percent estimated requirements vs. 90 to 100 percent estimated requirements)
  • Target blood glucose concentration (80 to 110mg/dL vs. 180 to 200mg/dL). 

Control Variables

Dextrose and propofol infusions were included in daily calorie intake calculations. Additional protein (Resource Beneprotein) was provided to the permissive underfeeding group to avoid protein malnutrition.

Description of Actual Data Sample:
  • Initial N: 240 (37% male)
    • 152 females
    • 88 males
  • Attrition: 240; zero lost to follow-up. Data were analyzed if the intervention was discontinued. 
  • Age:
    • 50.3 years (permissive underfeeding group)
    • 51.9 years (target feeding group) (P=0.56)
    • 53.0 years (intensive insulin therapy group)
    • 49.3 years (conventional insulin therapy group) (P=0.19)
  • Ethnicity: Not described
  • Other relevant demographics: Participants were matched on other baseline characteristics
  • Anthropometrics:
    • Participants were matched on age, female sex, height, weight, and body mass index 
    • APACHE II Scores permissive underfeeding group 25.2±7.5 and target feeding group 25.3±6.8 (P=0.89)
  • Location: Medical-surgical intensive care unit in a tertiary care academic hospital, Saudi Arabia.


Summary of Results:

Key Findings

  • Hospital mortality was statistically significantly lower in the permissive underfeeding group than in the target feeding group (P<0.04)
  • Other mortality outcomes were not statistically significant
  • The achieved calorie intake between the permissive underfeeding group and the target feeding group was statistically significant (P<0.0002); the average calorie intake between the two groups was statistically significant (P<0.0004); the achieved protein intake between the two groups was similar (P=0.14).
  • Other end-points were not statistically significant
  • There were no differences in end-points between the intensive insulin therapy and conventional insulin therapy groups.


Target Feeding(n=120)

Permissive Underfeeding

Statistical Significance of Group Difference

Intensive Insulin Therapy 
Conventional Insulin Therapy 
Statistical Significance of Group Difference
28-day all cause mortality  28 (23.3%)  22 (18.3%) P=0.34 23 (19.2%) 27 (22.5%) P=0.52 
180-day mortality  52 (44.4%) 38 (32.8%) P=0.07  45 (38.1%) 45 (39.1%) P=0.88 
Intensive Care Unit mortality  26 (21.7%) 21 (17.5%) P=0.42  26 (17.5%) 26 (21.7%) P=0.42 
Hospital mortality  51 42.5%) 36  (30%) P<0.04  42 (35%) 45 (37.5%) P=0.69 
Intensive Care Unit length of stay (days)  14.5±15.5  11.7±8.1 P=0.09  13.1±9.8  13.1±14.7 P=0.95 
Hospital length of stay (days)  67.2±93.6  70.2±106.9  P=0.81  76.7±106.3  66.7±94.3  P=0.76 
Mechanical ventilation duration (days)  13.2±15.2  10.6±7.6  P=0.10  11.6±8.6  12.1±14.8  P=0.74 




Author Conclusion:

Permissive underfeeding is associated with decreased morbidity and mortality than with target feeding in critically ill patients. Intensive insulin therapy is not associated with better outcomes relative to conventional insulin therapy. No statistically significant treatment effect was found in the primary end-point (28-day mortality); however, a decrease in both hospital and 180-day mortality rates was observed with permissive underfeeding. 

Funding Source:
University/Hospital: King Abdulaziz City for Science and Technology
Reviewer Comments:


  • Achieved calorie intake in target group was lower than planned (actual intake was 71 percent estimated requirement, not the planned 90 to 100% estimated requirement), resulting in a smaller difference between the interventions
  • Permissive underfeeding may not have been low enough to see benefit
  • Sample size may have been underestimated
  • End-point of 28-day mortality may not have detected the effect of the intervention; longer-term outcome measures may be better end-point
  • Monocenter
  • Unblinded.


  • 2x2 factorial, randomized design
  • Supplemental protein use; both groups maintained similar protein intakes.
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) 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)? 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? Yes
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