CI: Enteral Nutrition Energy Delivery (2012)


Heyland DK, Cahill NE, Dhaliwal R, Wang M, Day AG, Alenzi A, Aris F, Muscedere J, Drover JW, McClave SA. Enhanced protein-energy provision via the enteral route in critically ill patients: A single center feasibility trial of the PEP uP protocol. Crit Care. 2010; 14 (2): R78.

PubMed ID: 20429886
Study Design:
Non-Randomized Controlled Trial
C - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

The purpose of this pilot study was to assess the feasibility, acceptability and safety of "The Enhanced Protein-Energy Provision via the Enteral Route in Critically Ill Patients: The PEP uP Protocol."

Inclusion Criteria:
  • Consecutive mechanically ventilated adult patients (>18 years old)
  • Remained in intensive care unit (ICU) for ≥72 hours.
Exclusion Criteria:
  • Extubated before 72 hours
  • Transferred out of ICU before 72 hours.
Description of Study Protocol:


Consecutive admissions to a 21-bed medical surgical tertiary care ICU.


Non-Randomized Controlled Trial


Enteral nutrition (EN) practice before intervention:

  • If EN ordered, once tube position confirmed, nurse starts standard polymeric feeding formula at 25ml per hour
  • Gastric residual volume (GRV) monitored every four hours
  • Feeds advanced by 25ml per hour every four hours unless GRV >200ml
  • If GRV >200ml two or more times, feeds are reduced by 25ml per hour and nurse is instructed to ask doctor to order a gastrointestinal prokinetic agent; first metoclopramide, then erythromycin (if appropriate)
  • Dietitian assess nutritional needs, prescribes appropriate solution and hourly rate within 24 to 48 hours of admission.

Enteral nutrition practice after intervention (PEP uP Protocol):

  • Pre-printed order form at patient bedside with algorithms and instructions with tick boxes to indicate the following:
    • Full volume feeds, trophic feeds or NPO
      • Indications and contraindications for each selection were listed
    • Use of motility agent (in absence of contraindications)
      • Metoclopramide, 10mg intravenously every six hours, adjusted for renal failure
    • Initiation of protein supplement (14mg twice daily, providing 24 grams of protein per day)
  • Nurses given instructions on how to set hourly rate based on 24-hour volume prescription
  • Maximum hourly rate was arbitrarily set at 150ml per hour
  • GRV threshold set at 250ml, if GRV exceeded 250ml, erythromycin added
  • One formula was used initially, a semi-elemental, concentrated feeding solution (Peptamen 1.5, the dietitian could suggest changes after protocol was started.

Statistical Analysis

  • Categorical variables were reported as counts and percents, compared between cohorts by Fisher's Exact test
  • Length of stay variables described by medians and quartiles, compared by log-rank test
  • Continuous variables described by means and standard deviations, compared by Wilcoxon-Mann-Whitney test
  • Total energy and protein received from EN, parenteral nutrition or propofol was divided by amount of energy prescribed per baseline assessment, thus nutritional adequacy was expressed as a percentage
  • Those who did not receive EN were excluded from assessment of EN adequacy
  • All tests were two-sided
  • Statistical significance <0.05
  • SAS v9.1.3 (SAS Institute Inc., Cary, North Carolina, USA).
Data Collection Summary:

Timing of Measurements

  • The following data were retrospectively collected related to the prospectively enrolled patients for both groups: Admission category (surgery vs. medical), primary admission diagnosis, sex, age, weight, height, Acute Physiology And Chronic Health Evaluation II (APACHE II) score
  • The following data were collected daily for a maximum of 12 days of until death: Goal calories and protein per dietitian's assessment, type and and amount of nutrition received, morning blood glucose.

Dependent Variables

  • Primary outcome: Feasibility of a new feeding protocol as judged by a nursing questionnaire that evaluated their opinions of its safety and acceptability
    • Using a bedside questionnaire in the after group, nurses were asked about acceptability of each part of the feeding protocol and the overall protocol using a scale where 1=total unacceptability and 10=total acceptability
  • Secondary outcomes included nutritional endpoints (adequacy of EN, timeliness of EN initiation) and safety end-points (episodes of vomiting, aspiration and pneumonia).

Independent Variables

  • Before-intervention tube feeding protocol
  • After-intervention PEP uP protocol.
Description of Actual Data Sample:
  • Initial and final N:
    • 20 patients in before (control) group (55.0% male)
    • 30 patients in after (protocol) group (56.7% male)
  • Age: Mean age was
    • 59.5±17.3 years in the before (control) group
    • 64.4±16.7 years in the after (protocol) group
  • Ethnicity: Not reported
  • Anthropometrics: There were NS differences in baseline characteristics between study groups
    • APACHE II scores: control 20.7±6.9 and protocol group 21.3±7.3 (P=0.73)
  • Location: Kingston, Ontario, Canada.



Summary of Results:

 Key Findings

  • Nurses (n=30) rated acceptability of the protocol as follows (range one to 10, 1=total acceptability, 10=total unacceptability): 
    • Acceptability of the 24-hour volume based target 7.0
    • Acceptability of starting at a high hourly rate 5.9
    • Acceptability of starting motility agents right away 7.4
    • Acceptability of starting protein supplements right away 7.6
    • Acceptability of overall protocol 7.1
  • Average time to starting EN was 16.0 hours in before group and 17.7 hours in after protocol group (P=0.72)
  • Average calories and protein prescribed were 24 to 26kcal per kg and 1.1 to 1.2 grams of protein per kg across both time periods
  • In the before group, patients received an average of 58.8% of their energy and 61.2% of their protein needs by EN vs. 67.9% and 73.6% in the after group (P=0.33 and 0.13, respectively)
  • When a subgroup of patients prescribed to receive full volume feeds were evaluated (N=18), they received an average of 83.2% of calories and 89.4% of protein needs (P=0.02 and 0.002, respectively)
  • In the after group, 23.3% of patients were started on a motility agent on the first ICU day compared with 0% in the before group (P=0.03)
  • In the after group, 30.0% of patients were started on supplemental protein on the first ICU day vs. 0% in the before group (P=0.007)
  • There were no differences in EN related complications between groups.

 Other findings:

There was no power analysis, and purpose of study was to test for feasibility of protocol, clinical outcomes reported were:

Clinical Outcomes

Before Protocol


After PEP uP Protocol


Mortality within 60 days of ICU admission (%) 10% 30% 0.16
ICU LOS median days (IQR) 17.9 (11.2 to 47.8) 9/5 (4.9 to 12.7) 0.14
Hospital LOS median days (IQR) 57.4 (36.3 to undefined*) 22.9 (18.0 to 46.6) 0.02
Length of mechanical ventilation median days (IQR) 11.8 (7.6 to 43.3) 5.8 (3.6 to 8.6) 0.06
*Undefined because 44% (8/18) of surviving patients remained in hospital 60 days after ICU admission


Author Conclusion:

This new feeding protocol has the potential to dramatically improve nutrition practice world wide. This study introduces key philosophical and practical changes to have EN is prescribed and delivered to critically ill patients. In the context of a single-center, before and after study, the new PEP uP Protocol is safe, feasible and may improve nutritional adequacy. This study justifies the need for a larger multi center, multinational RCT to further determine the safety and efficacy of this novel approach to feeding the critically ill patient.

Importance notes:

  • Traditional enteral feeding protocols do not adequately provide sufficient protein and calories to critically ill patients
  • A new feeding protocol that challenges traditional assumptions and incorporates innovative ideas on maximizing the benefits and minimizing the risks of EN is needed
  • The PEP uP Protocol uses 24-hour volume-based feeding goals instead of hourly rate targets, initiating motility agents and protein supplements on Day 1, liberalizing the GRV threshold, and option to use trophic feeds
  • This new feeding protocol seems to be safe and acceptable to critical care nurses
  • Adoption of this protocol may be associated with enhanced delivery of EN, though further trials are warranted to evaluate its effect on nutritional and clinical end-points.
Funding Source:
Nestle Canada
Pharmaceutical/Dietary Supplement Company:
University/Hospital: Queen's University/Kingston General Hospital
Reviewer Comments:


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.) N/A
  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? 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? 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? 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? 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? N/A
  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)? N/A
  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? Yes