EAL

CI: Immune-Modulating Enteral Nutrition (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To compare the mortality of critically ill patients given either enteral feeding with an immune enhancing formula (IED) enteral nutrition (EN) or parenteral nutrition (PN). An interim analysis on patients with severe sepsis was undertaken earlier than planned, after a meta-analysis suggested excess mortality in patients with severe sepsis given enteral immunonutrition.

Inclusion Criteria:

Patients >18y, who were judged to need artificial ventilation and nutrition support for >4d, as defined by the attending physician.

Exclusion Criteria:

Motor Glasgow Coma Scale <4, pure cerebral disease, spinal trauma, and referral from ICUs in which patients stayed >24h.

Description of Study Protocol:

Design

Eligible patients were randomized to receive either total PN (59% carbohydrate, 23% fat, 18% protein, 1.2 kcal/mL) or IED EN (55% carbohydrate, 25% fat, 21% protein, 1.3 kcal/mL). All feedings were started within 48h from ICU admission. PN (25-28 total kcal/kg/d) was not integrated with IED EN before day 6 from randomization. EN was started at 10 kcal/kg and progressed to 25-28 kcal/kg by day 4.

Blinding used

Random patient assignment, the analyst was not blinded to group assignment. All the analyses, except 28d mortality, were planned.

Intervention

The IED EN used was Perative (Abbott), containing extra L-arginine (6.8g/L), omega-3 fatty acids (1.5g/L), Vitamin E (29mg/L), beta carotene (7.5mg/L), zinc (22 mg/L), and selenium (70 mg/L).

Statistical Analysis

Analysis was by intention to treat. As designed, risk of death was to be compared by the Mantel-Haenszel chi-squared test. Considering the smaller-than-planned sample size, Fisher exact test was used to determine the significance of ICU mortality and 28-day mortality in the subgroup with severe sepsis or septic shock at randomization. Effect size was expressed in terms of absolute risk difference with its 95% confidence interval.

A logistic regression model was used to analyze the difference in treatment effect according to presence or absence of severe sepsis (test of interaction), adjusting for possible confounders: total calories/kg received in the first 3 days, age >60y, respiratory and cardiovascular failure on admission, and gender. Adjusted analysis was determined for “total calories/kg received in the first 3 days” only. Adjustment for the other variables was suggested by their relative imbalance at baseline.

Data Collection Summary:

Timing of Measurements

The following were recorded: socio-demographic characteristics, acute diagnostic profile, Simplified Acute Physiology Score II (SAPS II) variables, length of stay (LOS), vital status at ICU discharge and 28d from randomization.

The following were recorded daily: nutritional regimen, classification of the septic condition (American College of Chest Physicians and Society of Critical Care Medicine criteria, ACCP/SCCM), Sepsis-related Organ Failure Assessment (SOFA) score, and Nine Equivalentsl of nursing Manpower use (NEMS) score.

Dependent Variables

Mortality at day 28.

Two additional subgroup analyses based on septic condition. ICU mortality was measured in the subgroup with severe sepsis or septic shock at randomization.

Independent Variables

Enteral nutrition enhanced with L-arginine (6.8g/L), omega-3 fatty acids (1.5g/L), Vitamin E (29mg/L), beta carotene (7.5mg/L), zinc (22 mg/L), and selenium (70 ug/L). Feedings were progressed to goal of 25-28 total kcal/kg/d.

Control Variables

Parental nutrition, goal of 25-28 total kcal/kg/d.

Description of Actual Data Sample:

Initial N:

The study was designed to enroll 1,500 patients. An interim analysis was planned to take place after 750 patients were enrolled. At the time of the early interim analysis, 289 patients were eligible for the study, while 52 of those were not included.

Attrition (final N):

Early interim analysis was conducted after 237 patients had been enrolled within 33 ICUs. Of those, 39 had severe sepsis and three of the patients were initially randomized as being without sepsis, but subsequently analyzed among the patients with severe sepsis since each met the criteria.

18 patients were fed the IED EN, 21 were fed PN.

Age:

Age, mean + SD (y): IED EN=59.3+17.6; PN=59.0+21.4

Percentage of patients >60y: IED EN=50%; PN=67%

Other relevant demographics:

Gender of patients (% female): IED EN=39%; PN=52%

Percentage of patients with unfavorable prognoses (% of patients with respiratory and cardiovascular failure): IED EN=61%; PN=81%

Anthropometrics:

No other differences observed between groups

Location:

Adult ICUs adhering to the Gruppo italiano per la Valutazione degli interventi in Terapia Intensiva (GiViTI).

Summary of Results:

	Immune-Enhancing Diet Enteral Nutrition (n=18)	Parenteral Nutrition (n=21)	Absolute Risk Difference, (Confidence Interval)
ICU Mortality	n=8 (44%)	n=3 (14.3%)	30.1, (1.5-58.7)p=0.039/p=0.072
28-day Mortality	n=8 (44%)	n=5 (23.8%)	20.6, (-9.4-50.6)p=0.179/p=0.196
Continued Prevalance of Sepsis at Time of Death	n=7 (39.9%)	n=2 (9.5%)	Fisher's p=0.055

Immune-Enhancing Diet Enteral Nutrition (n=18)

Parenteral Nutrition (n=21)

Absolute Risk Difference,
(Confidence Interval)

ICU Mortality

n=8 (44%)

n=3 (14.3%)

30.1, (1.5-58.7)p=0.039/p=0.072

28-day Mortality

n=8 (44%)

n=5 (23.8%)

20.6, (-9.4-50.6)p=0.179/p=0.196

Continued Prevalance of Sepsis at Time of Death

n=7 (39.9%)

n=2 (9.5%)

Fisher's p=0.055

Day	Immune-Enhancing Diet Enteral Daily Caloric Intake (kcal/kg/d)	Parenteral Nutrition Daily Caloric Intake (kcal/kg/d)	Percentage of mean daily caloric intakes, EN compared to PN (%) (mean EN/mean PN x 100)
1	9.4 (1.8)	17.6 (6.4)	50%
2	13.7 (4.5)	27.3 (4.9)	53%
3	19.9 (3.0)	27.8 (4.5)	72%

Other Findings

median ICU LOS (d): IED EN=13.5; PN=15.

All three logistic regression models of dietary interaction confirmed a worse outcome in severely septic patients receiving the IED EN: Model 1: unadjusted analysis, OR=4.8. Model 2: (planned) adjusted analysis for caloric intake, OR=2.4. Model 3: (unplanned) adjusted analysis for caloric intake and unbalanced baseline characteristics, OR=3.1.

As a result of the interim analysis, intervention in severely septic patients was stopped.

Author Conclusion:

Results show that enteral immunonutrition, compared to PN, may be associated with excess mortality in patients with severe sepsis. IED EN is not better than PN in patients with severe sepsis. Furthermore, IED EN, including diets supplemented with arginine and other immunomodulating additives, is not a desirable treatment option in this patient population.

Funding Source:

Industry:

Abbott Italia (Italy)

Pharmaceutical/Dietary Supplement Company:

Reviewer Comments:

The group adapted statistical analyses to accommodate the smaller-than-planned sample sizes.

There is a significant difference between groups in average total kcal/d during feeding days 1-3. It is questionable whether increased caloric intake via the PN feeding route contributed to improved outcomes in the experimental group.

While the study does warrant that IEDs be held from severely septic patients, the study does not demonstrate that the treatment option of standard EN is less desirable than PN in patients with severe sepsis.

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?	???
	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.)	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?	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?	???
	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?	???
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