CI: Monitoring Delivery of Energy (2006)

Citation:

Atkinson S, Sieffert E, Bihari D. A prospective, randomized, double blind, controlled clinical trial of enteral immunonutrition in the critically ill. Critical Care Medicine, Vol 26(7) July 1998: 1164-1172

PubMed ID: 9671364
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To assess the effects of enteral immunonutrition (IMN) on hospital mortality and length of stay in a heterogeneous group of critically ill patients.

Inclusion Criteria:

Expected to stay for >= 3 days in ICU. To assess the expected ICU stay, used Acute Physiology and Chronic Health Evaluation (APACHE) II >10, TISS score > 20, and clinical assessment by the attending intensive care specialist.

Exclusion Criteria:
  • Contraindications to the use of enteral nutrition
  • < 16 years of age
  • Absence of informed consent from pt or relatives
  • Description of Study Protocol:

    A prospective, randomized, double-blind, single-center, controlled clinical trial of the use of two formulations of enteral conducted in a 13-bed, general ICU in London. Within 48 hours of ICU admission, they were randomized to receive either immunonutrition Impact, supplemented with L-arginine, RNA, and omega-3 fatty acids, or a specially manufactured, isocaloric (1kcal/mL), isonitrogenous (16.55 g of N/1500 mL) identical to Impact in its vitamin and trace element profile and appearance.  To render control feed isonitrogenous, it was supplemented with L-serine, glycine, L-alanine, and L-proline.

    Target rate of delivery in all cases was 32 kcal/kg/day and 1.8 g protein/kg/day.

    Routes of delivery were nasogastric, nasojejunal, and surgical jejunostomy.

     

    Data Collection Summary:

    Primary end point was all-cause in hospital mortality, stratified a priori by the volume of enteral feed delivered.

    Secondary outcomes measured:

    • duration of ventilation
    • duration of systemic inflammatory response syndrome (SIRS) (ICU days of SIRS per patient
    • post randomization intensive care and hospital length of stay

    The requirement for therapeutic intervention within the ICU, which was quantified using daily Therapeutic Intervention Scoring System (TISS) scores  

    Successful early enteral nutrition was defined as >2.5 L of enteral nutrition in the first 72 hrs after ICU admission.

     

    Description of Actual Data Sample:

    A total of 398 pt were enrolled and data from 390 (IMN=103, control=197) were used for intention-to-treat analysis. 369 patients (IMN=184, control=185) who actually received some enteral nutrition, of whom 101 pt (IMN=50, control=51) received .2.5 L within 72 hours of ICU admission (successful early intervention group).  Groups were age and gender matched.

    Summary of Results:

    • Case mix heterogeneous, but similar between the two feed groups.
    • In the received feed cohort, the first 24-hr APACHE II and risk of hospital death was greater in the Impact group than the control group.
    • Rates of delivery were less than target (Impact group=14 kcal/kg/day;  Control group=13 kcal/kg/day)
    • Deaths rates and LOS were not statistically different between groups
    • In the intention-to-treat and received feed groups, there was no difference between the two feed groups for any measured variable.
    • When only looked at the early nutrition group, both duration of mechanical ventilation and post randomization length of hospital stay were significantly less in the Impact group than control group (duration of ventilation: Impact group 6 [1 to 40] days, control group 10.5 [1 to 204] days, p=0.007; length of hospital stay; Impact group 15.5 [3 to 111] days, control group 20 [2 to 289] days, p=0.03).
    • For the early enteral nutrition subgroup, a multiple linear regression model was developed to assess the effects of hospital outcome, formulation of feed, APACHE II score, risk of death in the first 24 hours of ICU admission, and therapeutic intervention (mean daily TISS) on post randomization length of hospital stay.  A log transformation of length of stay produced a better model.  Stepwise analysis excluded the APACHE II score and risk of death as having any effect.  Formulation of feed was retained and it had an independent effect in the model.

     

    Author Conclusion:

    This study was designed to assess the efficacy of the widespread use of immunonutrition in the critically ill, with an expected hospital mortality rate of >35%. The entry criteria was established to allow the randomization within a single center of a large number of pt with a broad range of diagnoses and risk of hospital death, thus more closely resembling usual clinical practice.  Our study design addressed the necessity of an intention-to-treat analysis.  Correctly randomized patients who did not receive any trial agent (early ICU deaths or trail withdrawals) were included in the analysis.  However, they also created a priori two specific cohorts or interest: a) those patients who received some enteral nutrition; and b) patients who received reasonable volumes of feed early on in their ICU course (>2.5 L within 72 hours of ICU admission).  Using this approach, while there was no benefit of immunonutrition on overall outcome in the intention-to-treat analysis, the study demonstrated that those patients who tolerated early enteral nutrition and were fed impact, there was a significant reduction in their requirement for mechanical ventilation, with an associated significant reduction in post randomization hospital length of stay.  If theses differences in outcome really did arise directly from the intervention  studied (i.e., enteral immunonutrition) as the multiple linear regression model suggests, then the trial provides additional evidence that it is not only important to achieve early enteral nutrition in the general ICU population, but also to achieve this goal with an “immune-modulating” feed.

    Funding Source:
    Industry:
    Novartis Nutrition Corporation
    Pharmaceutical/Dietary Supplement Company:
    University/Hospital: Guy's Hospital (UK)
    Reviewer Comments:

    Heterogeneous patient mix with overall mortality rate of 46% which reflects ICU patient population. As the authors suggest, sufficient feeding of at least 53% of needs may be necessary to so show benefits of enteral feeding.

    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) N/A
      2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? N/A
      3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? N/A
      4. Is the intervention or procedure feasible? (NA for some epidemiological studies) N/A
     
    Validity Questions
    1. Was the research question clearly stated? N/A
      1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? N/A
      1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? N/A
      1.3. Were the target population and setting specified? N/A
    2. Was the selection of study subjects/patients free from bias? N/A
      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? N/A
      2.2. Were criteria applied equally to all study groups? N/A
      2.3. Were health, demographics, and other characteristics of subjects described? N/A
      2.4. Were the subjects/patients a representative sample of the relevant population? N/A
    3. Were study groups comparable? N/A
      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? N/A
      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? N/A
      4.1. Were follow-up methods described and the same for all groups? N/A
      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%.) N/A
      4.3. Were all enrolled subjects/patients (in the original sample) accounted for? N/A
      4.4. Were reasons for withdrawals similar across groups? N/A
      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? N/A
      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.) N/A
      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? N/A
      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? N/A
      6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? N/A
      6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? N/A
      6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
      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? N/A
      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? N/A
      7.1. Were primary and secondary endpoints described and relevant to the question? N/A
      7.2. Were nutrition measures appropriate to question and outcomes of concern? N/A
      7.3. Was the period of follow-up long enough for important outcome(s) to occur? N/A
      7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? N/A
      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? N/A
      7.7. Were the measurements conducted consistently across groups? N/A
    8. Was the statistical analysis appropriate for the study design and type of outcome indicators? N/A
      8.1. Were statistical analyses adequately described and the results reported appropriately? N/A
      8.2. Were correct statistical tests used and assumptions of test not violated? N/A
      8.3. Were statistics reported with levels of significance and/or confidence intervals? N/A
      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? N/A
      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? N/A
      9.1. Is there a discussion of findings? N/A
      9.2. Are biases and study limitations identified and discussed? N/A
    10. Is bias due to study's funding or sponsorship unlikely? N/A
      10.1. Were sources of funding and investigators' affiliations described? N/A
      10.2. Was the study free from apparent conflict of interest? N/A