CI: Immune-Modulating Enteral Nutrition (2006)

Citation:

Cerra FB, Lehman S, Konstantinides N, Konstantinides F, Shronts EP, Holman R. Effect of enteral nutrient on in vitro tests of immune function in ICU patients:  A preliminary report. Nutrition. 6(1):84-87, 1990.

PubMed ID: 2135759
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:

To see if a balanced diet enriched with arginine, n-3 PUFA, and RNA would result in an improvement in in vitro tests of immune function after 7-10 days of therapy.

Inclusion Criteria:

ICU patients, age 21-80, who sustained a surgical event for which they were admitted into, and continued in, the ICU. Events included trauma, major elective surgery, and surgical infections. Each patient had to be minimally to moderately malnourished, under moderate metabolic stress, judged suitable for enteral nutrition for 7-10 days, and have the ability to tolerate all of the nutrition support via the enteral route.

Criteria for “malnutrition”:  clinical exam, serum albumin >2.5 <3.5g/dl, plasma transferring >150 <200mg/dl, weight/height >80% of normal, and weight loss <10% of actual body weight in the 3-4 weeks preceding the study.    

Criteria for “metabolic stress”:  level 1 = glucose 150+25mg/dl, urinary oxygen 5-10g/d, oxygen consumption index(VO2) 125+25ml/m2, level 2 = glucose 200+25mg/dl, urinary oxygen 5-10g/d, VO2 175+25ml/m2

Exclusion Criteria:

History of insulin-dependent diabetes mellitus, receiving steroids or chemotherapy, glomerular filtration rate by creatinine clearance <25ml/h, pregnancy, severe pancreatitis or hyperlipidemia, or history of severely impaired gastrointestinal function or malabsorption, such as short bowel syndrome.

Description of Study Protocol:

Recruitment

Design

A nasoenteric feeding tube was placed into the duodenum. Tube feedings were started at full-strength at 25ml/h, progressed 25ml/h at 12-hour increments until the required volume was achieved.  Daily calorie needs were calculated as 150% basal energy expenditure (BEE), using the Harris-Benedict equation to estimate BEE.

Blinding used (if applicable)

Double-blind.  Patients were randomized by the research pharmacy.

Intervention (if applicable)

Patients received either the “control” enteral formula, Osmolite HN, or the immune enhanced diet (IED) formula, Impact.  The control formula used was high in casein protein, lactose-free, contained almost 1.5 times more vitamin C, while the fat composition was 50% medium chain triglyceride (MCT) versus 25% in the study formula, and the non-protein calories to nitrogen ratios were 125:1 vs. 71:1, respectively.  The IED formula was high in protein and enriched in omega-3 fatty acids, arginine, RNA, and vitamins A and E.

Statistical Analysis

Data on Entrance Characteristics analyzed by one-way analysis of variance.

Data Over the Study Interval analyzed by two-way analysis of variance.

Immune Function Tests Over the Study Interval analyzed by regression analysis, a Z-score was determined for both control and experimental groups to determine change from time 0.  A Z-score was also determined between groups.  Significance was defined as p<0.05.

Data Collection Summary:

Timing of Measurements

The following were recorded: Days to Entrance (the variable time period patient was in the ICU prior to entering the study), Days to Goal (the variable time from inception of tube feedings to achieving the full dose).

On study days 0, 3, and 7-10, the following were recorded:  serum glucose, BUN, creatinine, liver function tests, platelet count, prothrombin time, triglyceride, albumin, and plasma transferring.  Additional blood was drawn for in vitro immune stimulation studies:  Con A, HA, and Tetanus. 

Urine and stool were collected daily to calculate nitrogen balance.

Dependent Variables

  • Nutrition Support Outcomes: 

                Calories/d

                Nitrogen (g/d)

                Nitrogen balance (g/d)

                Days to Goal

                Days on Goal

                Days in Study

                Change in albumin (mg%)

                Change in transferrin (mg%)

  • Patient Outcomes: 

                Days in Hospital

                Mortality

                Blood units given

  • Immune Function Tests, in vitro lymphoproliferative response to:

                Con A antigen

                HA antigen

                Tetanus antigen

Independent Variables

Enteral feeding with the IED Impact.  The formula is high in protein; enriched in omega-3 fatty acids, arginine, RNA, and vitamins A and E; and has a fat composition of 25% MCT and a non-protein calories to nitrogen ratio of 71:1

Control Variables

Enteral feeding with Osmolite HN.  The formula is high in casein protein, lactose-free, contains almost 1.5 times more vitamin C, a fat composition of 50% MCT and a non-protein calories to nitrogen ratio of 125:1.

Description of Actual Data Sample:

Initial N:

9 control patients; 13 IED patients       

Attrition (final N):

9 control patients; 11 IED patients (2 dropouts:  1 self-withdrew on day 1, one had feedings discontinued for >24h.)

Age:

Control: IED (mean+SE, years)  54.4+8.8 : 62.3+5.6

Ethnicity:

Other relevant demographics:

Gender was 75% male in both groups

Anthropometrics (e.g., were groups same or different on important measures)

Weight/ht Control: IED (mean+SE)  113+11.2 : 115+8.6

Location:

ICUs associated with the University of Minnesota.

Summary of Results:

Variables
In Vitro Stimulation

Treatment Group

Control group

Con A antigen:  (% change from baseline)

Intercept

Slope 

Statistical Significance

 


22.3 + 22.6

36.6 + 37.6

p<0.01

 


-2.4 + 3.7

-4.5 + 3.1

p=.065

HA antigen:  (% change from baseline)

Intercept

Slope

Statistical Significance 

 


7.4 + 7.3

14.4 + 8.5

p<0.01

 


-0.01 + 5.5

-4 + 0.99

p<0.01

Tetanus antigen:  (% change from baseline)

Intercept

Slope 

Statistical Significance 

 


26.2 + 15.4

33.0 + 21.5

p<0.01

 


7.9 + 11.7

-6.4 + 27

p<0.03

Other Findings

No differences in feedings administered, nutrition outcomes, mortality, or length of hospital stay between groups.

IED demonstrated statistically significant increased responsiveness in the 3 in vitro tests conducted at the mid-point and end of the study.  Conversely, the control diet was associated with a downward trend of responsiveness. 

Author Conclusion:

Immunocompetence, measured by in vitro stimulation of peripheral blood lymphocytes with three antigens, Con A, HA, and Tetanus, was significantly better at the mid-point and end of the study for the IED feeding group. Effects occurred within 7-10 days of enteral feeding.

Funding Source:
University/Hospital: University of Minnesota
Reviewer Comments:

Small data sample.

All patients had sepsis or sepsis syndrome.

This study suggests that the nutrient composition of Impact augments immune responsiveness in patients with sepsis or sepsis syndrome; whether this influences length of stay, infectious complications, and mortality was not determined.

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) 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? ???
  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)? ???
  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? No
  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? ???
  10.1. Were sources of funding and investigators' affiliations described? No
  10.2. Was the study free from apparent conflict of interest? ???