CI: Immune-Modulating Enteral Nutrition (2006)

Citation:

Brown RO, Hunt H, Mowatt-Larssen CA, Wojtysiak SL, Henningfield MF, Kudsk KA. Comparison of specialized and standard enteral formulas in trauma patients.  Pharmacotherapy. 14(3):314-320, 1994.

PubMed ID: 7937272
 
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 compare selected nutrition and immunologic markers and infection in trauma patients receiving a specialized enteral formula with those receiving standard enteral therapy.

Inclusion Criteria:
Adults, age 18-75, who sustained multiple trauma and required enteral nutrition support, initially hospitalized in a trauma- or neurosurgery intensive care unit. Patients who could not take an oral diet, had a functioning and accessible gastrointestinal tract.
Exclusion Criteria:

Patients with diabetes mellitus, pregnancy, renal failure, liver failure, metastatic carcinoma, gastrointestinal malabsorptive disorders, or known seropositivity for the human immunodeficiency virus.

Description of Study Protocol:

Design

Enteral nutrition support was initiated within 7 days of injury. Patients were enrolled in the study for a length of 5-10d. Patients were fed through nasogastric, gastrostomy, or jejunostomy routes.  Feedings were started at full-strength at 25-50ml/h, progressed 25ml/h as tolerated to a goal of 35 kcal/kg/d and 1.5 g protein/d.  Oral diets were prescribed when appropriate.  When oral intakes exceeded 25% of total calorie needs, counts for calories and protein were recorded. 

Blinding used (if applicable)

Random patient assignment, investigators were not blinded to type of formula.

Intervention (if applicable)

Patients received either the “control” enteral formula, Osmolite HN, supplemented with ProMod protein powder to obtain similar nitrogen content, or the immune enhanced diet (IED) formula.  The control formula used was high in intact casein protein, lactose-free, and had a fat composition of 50% medium chain triglyceride (MCT) versus 40% in the study formula.  The IED formula was high in total protein, contained partially hydrolyzed proteins and was enriched in L-arginine (2% total kcal), a-linolenic acid from canola oil, and b-carotene. 

Statistical Analysis

A two-sample Student’s t test was used on all continuous variables.  A Mann-Whitney test on ordinal data from study day 1 assessed comparability of groups at study initiation.  A Fisher’s Exact test was used to compare dichotomous demographic variables.  Analysis of covariance statistically adjusted for the difference between groups regarding length of time between hospital admission and starting the study. 

Two change scores were calculated for all serum chemistry data, day 1-day 5 and day 1-day 10.  Change scores were analyzed by one-way analysis of covariance.  Similar analyses were conducted for nitrogen balance.  Since change scores for urine output was nonnormally distributed, differences were ranked and analyzed using the Wilcoxon Sign Rank test.

Variables of Nutrient Intake were averaged for two time periods, day 1-day 5 and day 1-day 10.  Average daily amounts were analyzed by one-way analysis of covariance.

Variables coded with a ‘yes’ response, as opposed to a ‘no’ response, (eg. GI intolerance) were counted on days 1, 5, and 10 and compared by Fisher’s Exact test.

Results were considered statistically significant if p<0.05.  All data were expressed as means + SEM.      

Data Collection Summary:

Timing of Measurements

The following were recorded: hospital admission trauma and injury severity scores, APACHEII scores and presence of infection on study entry, age, height, weight, BMI, primary and secondary diagnoses, drug therapy.

Patients were observed daily for septic morbidity, including:  pneumonia, wound infection, urinary tract infection, sinus infection, and bacteremia.

Patients were observed daily for gastrointestinal intolerance including elevated gastric residuals and diarrhea.  Treatment of Elevated Gastric Residuals involved holding enteral feeds for at least 4h. 

On days 1, 5, and 10 of enteral nutrition:  serum was measured for prealbumin, C-reactive protein, fibronectin, and colloid oncotic pressure; SMA-24 was conducted to measure electrolytes, carbon dioxide, glucose, blood urea nitrogen, creatinine, phosphorous, calcium, magnesium, cholesterol, total protein, and albumin; a 24-hour urine collection was used to calculate nitrogen balance.

At study entry and exit, T lymphocyte subpopulations (CD4 and CD8) were measured.

Dependent Variables

  • Variables of Nutrient Intake:  enteral rate, volume, kcal, enteral protein.
  • Outcome Variables: 

                Length of hospital stay

                Days on ventilator

                Days in ICU

                Colloid oncotic pressure

  • Serum Proteins: 

                Albumin

                Prealbumin

                C-reactive protein

                Fibronectin

                Immune Status Markers:  CD4:CD8 ratio

Independent Variables

Enteral feeding with the immune enhanced diet (IED) formula, high in total protein, containing partially hydrolyzed proteins, supplemental L-arginine (2% total kcal), a-linolenic acid from canola oil, and b-carotene. 

Control Variables

Enteral feeding with Osmolite HN, supplemented with ProMod protein powder to obtain similar nitrogen content.  The formula is high in intact 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:

Forty-one patients (20 control patients; 21 IED patients)

No statistical differences in age, sex, BMI, trauma score, injury severity score, or APACHEII score.

Attrition (final N):

Thirty-seven patients (18 control patients; 19 IED patients).  Two patients were excluded from each group, as additional operative procedures prevented initiation of enteral feedings within 7 days of injury.

Age:

Control: IED (mean+SE, years)  27+2 : 31+3

Ethnicity:

Other relevant demographics:

Gender, Control: IED (%female)  22 : 16

The majority of patients in both groups suffered injury due to motor vehicle accidents.

Anthropometrics

No significant differences between groups

Location:

A level I trauma center at a county government hospital, the Regional Medical Center at Memphis, Tennessee.

Summary of Results:

 

Variables

Treatment Group Control group

Statistical Significance of Group Difference

Initiation of Enteral Feedings (average days after admission) 3.5 5.0 Not stated

Days with Elevated Gastric Residuals (% of Total Enteral Feeding Days)

5.3 10.2 Not stated
Days Patients Met >85% of Their Feeding Goals (% of Study Days) 47 23 Not stated
Average Daily Calorie Intake (kcal/kg/day) 25 20 Not stated
Average Daily Protein Intake (g/kg/day) 1.32 1.27 NS
Change in Nitrogen Balance, study day1 vs. study day5 (g N/day) -7.3+1.7     vs. -7.4+2.8 -11.8+1.8 vs. -5.9+2.0 p<0.02
Frequency of Septic Morbidity after study entry in patients consistently meeting >85% of caloric goals (% of patients) 7.7 50 p<0.05
Change in C-reactive protein, study day 1 vs. study day 5 (mg/dl) 18.0+2.1 vs. 11.8+1.5 17.6+1.3 vs. 14.4+1.7 p<0.05
Number of patients, who consistently met >85% of their feeding goals, remaining in the ICU after 5 days of enteral feedings (% of patients) 54 75 trend

Other Findings:               

Serum prealbumin and fibronectin concentrations increased significantly from baseline in both groups; however, changes were not significantly different between groups.

Author Conclusion:

Trauma patients who received the specialized enteral formula demonstrated a decreased incidence of infection and increased improvements in nitrogen balance and another index of stress, C-reactive protein.

Additional clinical trials demonstrating positive patient outcomes are necessary before these specialized enteral formulas are used as the standard of practice in critically ill patients.

Funding Source:
Industry:
Ross Laboratories
Food Company:
University/Hospital: University of Tennessee, Memphis State University
Reviewer Comments:

Small data set, especially considering the subset of patients who consistently met >85% of their feeding goals.

The formulas were similar in total nitrogen content, 63.0 : 66.6 g/L (control:IED).

Patients receiving the IED were fed significantly earlier and received more calories.  While all patients were fed within 7 days of admission, average time of enteral feeding initiation was 5.0 : 3.5 days after admission (control:IED).  It is questionable whether this time period is early enough to provide clear benefit of enteral nutrition.  Average daily intakes were 20 : 25 kcal/kg/day (control:IED).  When only data from those who consistently met their feeding goals were analyzed, no statistical differences were noted.  It is questionable whether increased caloric intake contributed to improved outcomes in the experimental group. 

The various feeding routes may have contributed to outcomes.  For example, prepyloric feeding may increase prevalence of pneumonia and elevated gastric residuals with gastric feedings lead to reduced intakes when enteral nutrition is infused over a 24-hour period.  In this study, jejunal feedings correlated with patients meeting >85% of caloric goals for the day.

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? ???
  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? ???
  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? 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? ???