EAL

CI: Initiation of Enteral Nutrition (2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To evaluate the effect of early enteral nutrition on the outcome of critically ill and injured patients.

Inclusion Criteria:

Randomized, controlled clinical trials
All relevant randomized, controlled trials (RCTs) that compared early with delayed enteral nutrition. An RCT was defined as a trial in which subjects were assigned prospectively to one of two interventions by random allocation. Authors used a multiple-method approach to identify relevant studies for this review. A computerized literature search of the National Library of Medicine’s MEDLINE from 1966 to August 2000 was conducted using the following search terms: “enteral nutrition (explode)” and “early or immediate or delayed” and “randomized controlled trials (publication type)” or “controlled clinical trials” or “clinical trials, randomized.”
Bibliographies of all selected articles and review articles that included information on enteral nutrition were reviewed for other relevant articles. In addition, each author reviewed his personal files and contacted experts in the field. This search strategy was done iteratively, until no new potential, RCT citations were found on review of the reference lists of retrieved articles.
The selection criteria were used to identify published studies for inclusion in this analysis: a) study design: randomized clinical trial; b) population: hospitalized adult post-operative, trauma, head-injured, burn or medical ICU patients; c) intervention: early vs. late/delayed institution of enteral nutrition; and d) outcome variables: at least one of the following primary outcome variables: the number of infections, total number of non-infectious complications, length of hospital stay (LOS) and hospital mortality. For the purposes of this meta-analysis, early enteral nutrition was defined as the initiation of enteral feeds within 36 hours of admission to the hospital or within 36 hours of surgery. Delayed enteral nutrition was defined as nutritional support that was initiated after 36 hours of admission to the hospital or after 36 hours of surgery. Study selection and data abstraction was conducted independently by the two investigators.

Exclusion Criteria:

Five articles were excluded for the following reasons: Nocturnal protein supplementation was compared with control
Three studies with enteral nutrition was delayed for 36 hours in the early feeding group, with feeding delayed for up to 57, 60, and 96 hours
One study where the control group was not randomized.

Description of Study Protocol:

All relevant randomized, controlled trials (RCTs) that compared early with delayed enteral nutrition. An RCT was defined as a trial in which subjects were assigned prospectively to one of two interventions by random allocation. Authors used a multiple-method approach to identify relevant studies for this review. A computerized literature search of the National Library of Medicine’s MEDLINE from 1966 to August 2000 was conducted using the following search terms: “enteral nutrition (explode)” and “early or immediate or delayed” and “randomized controlled trials (publication type)” or “controlled clinical trials” or “clinical trials, randomized.”
Bibliographies of all selected articles and review articles that included information on enteral nutrition were reviewed for other relevant articles. In addition, each author reviewed his personal files and contacted experts in the field. This search strategy was done iteratively, until no new potential, RCT citations were found on review of the reference lists of retrieved articles.
Randomized, controlled studies that compared early with delayed enteral nutrition in hospitalized adult post-operative, trauma, head-injured, burn or medical intensive care unit (ICU) patients. From 161 articles screened, 27 were identified as RCTs comparing early with delayed enteral nutrition and were included for data extraction. Of these, 12 were excluded. None of the studies included medical ICU patients.
Fifteen studies containing 753 subjects were analyzed. Descriptive and outcome data were extracted independently from the articles by the two reviewers. Main outcome measures were infections, non-infectious complications, LOS and mortality. The meta-analysis was performed using the random effects model.
Early enteral nutrition was defined as the initiation of enteral feeds within 36 hours of admission to the hospital or within 36 hours of surgery. Delayed enteral nutrition was defined as nutritional support that was initiated after 36 hours of admission to the hospital or after 36 hours of surgery. Study selection and data abstraction was conducted independently by the two investigators.
Infections, complications and mortality were treated as binary variables. Length of hospital stay was treated as a continuous variable. The data analysis was performed using the random effects model with meta-analysis software (RevMan 4.1, Cochrane Collaboration, Oxford, UK). The relative risk and continuous data outcomes are presented with 95% confidence intervals.

Data Collection Summary:

At least one of the following primary outcome variables: The number of infections, total number of non-infectious complications, length of hospital stay (LOS) and hospital mortality
LOS was treated as a continuous variable. The relative risk and continuous dataoutcomes are presented with 95% confidence intervals. Authors reported standard deviations (SD), we used them directly. When SD were not available, they computed them from the observed mean differences (either differences in changes or absolute readings) and the test statistics.
The data analysis was performed using the random effects model with meta-analysis software. Subgroup analyses were performed on each of the postoperative trauma, head-injured and burn groups for each outcome variable.
Authors found no studies that met the inclusion criteria for medical ICU patients. These subgroups were chosen because they reflect the main clinical populations included in the trials.

Description of Actual Data Sample:

161 articles screened
27 identified
15 trials (studies) containing 753 subjects included for meta analysis. Twelve studies are excluded.
Articles were excluded for the following reasons: Nocturnal protein supplementation was compared with control (N=5)
An enteral nutrition was delayed for 36 hours in the early feeding group, with feeding delayed for up to 57, 60, and 96 hours (N=3). The control group was not randomized (N=1). Pediatric patients were included (N=2) and patients in the treatment group received parenteral nutrition in addition to enteral nutrition (N=1).
Overall, 753 patients were enrolled in the included studies. In none of the studies was their crossover to the other arm of the study. It is important to note that no studies of medical ICU patients were found.
Subgroup analyses, post-operative: Trauma, head-injured and burn groups for each outcome variable; significant heterogeneity between trials.

Summary of Results:

Infections

Information on the incidence of infections was available for 12 of the 15 (80%) studies and included 603 patients
There was a significantly lower risk of infection in the patients who received early enteral nutrition (relative risk of 0.45; 95% confidence interval [CI], 0.30–0.66; P<0.00006)
Infectious complication occurred in 19% of the early nutritional group as compared with 41% in the delayed group. The test for heterogeneity between the studies just reached statistical significance (P<0.049).

Non-infectious Complications

Information on the incidence of non-infectious complications was available for nine of the 15 studies (60%)
The incidence of non-infectious complications was 33% in the early group compared with 38% in the delayed group. This difference was not significant (relative risk, 0.82; 95% CI, 0.56–1.19).

Length of Hospital Stay

Information on LOS was available for 12 of the 15 studies (80%)
The LOS was significantly shorter in the early nutrition group (P<0.0012; mean reduction of 2.2 days; 95% CI, 0.81–3.63 days)
The reduction in LOS was most marked in the trauma/head injured/burn patients (4.04 days with 95% CI of 1.28–6.81days; P<0.004)
There was significant heterogeneity between studies (Chi square=30.7; P<0.0012).

Mortality

Information on hospital mortality was available for only six of the 15 (40%) studies
The mortality was 8% in the early group and 11.5% in the delayed nutrition group; this difference was not significant (relative risk, 0.74; 95% CI, 0.37–1.48)
There were no significant differences in mortality or non-infectious complications between the two groups of patients.

Summary of Nutritional Support of the Studies Included in Meta-analysis

Date Author	N	Study Protocol	Formula	Caloric Intake (kcal) or % of Goal; Control vs. Intervention (Mean ±SD)
Abdominal surgery
1979 Sagar	30	SBT < 24 hrs	Elemental diet	Day 2; 300±20 vs. 1,100±100
1991 Schroeder	32	SBT < 24 hrs	Standard	isocaloric Days 1–4; 382±71 vs. 1179±338
1995 Hasse	31	SBT < 24 hrs	Oral standard	isocaloric Day 3; 550 vs.1,900
1996 Beier-Holgersen	60	SBT< 4 hrs	Nutrition supplement	Day 3 (median); 0 vs.1,500
1996 Carr	28	SBT< 2 hrs	Standard	isocaloric Days 1–4; 377±34 vs. 1,622±375
1997 Watters	28	Jejun < 2 hrs	Standard	isocaloric Day 3; 0 vs.1,500
1997 Heslin	164	Jejun < < 24 hrs	Immune	enhancing diet Day 3, % goal; 22% vs. 58%
1997 Schilder	94	Oral intake < 24 hrs	Blenderized liquid diet	--
1998 Singh	43	Jejun< 12 hrs	Liquid diet	Day 4; 406±89 vs. 2,116±243
Trauma 1984 Seri	18	Jejun < 12 hrs	Blenderized liquid diet	— —
1986 Moore	63	Jejun< 24 hrs	Elemental diet	Day 4, % goal; 36±2% vs. 156±11%
1998 Kompan	28	OG < 6 hrs	Standard isocaloric	Day 4; 703±701 vs. 1,340±473
Head injury 1989 Grahm	32	SBT < 36 hrs	Elemental diet	Day 3; 411 vs 2,499
1999 Taylor	82	OG/SBT < 24 hrs	Hypercaloric (1.5 kcal/ml)	Day 2% of goal; 20% vs. 58%
Burns 1990 Chiarelli	20	< 24 hrs	Blenderized liquid diet	__ __

SBT, small bowel tube; jejun, jejunostomy; OG, orogastric tube; —, data not available.

Summary of Outcomes Data of Studies Included in Meta-analysis

Date Author	N	Study Protocol Control vs.	Outcome Variables (Control vs. Intervention)
			Mean LOS (days)	Infections	Other Comp-lications	Mortality
Abdominal surgery 1979 Sagar 1991 Schroeder 1995 Hasse 1996 Beier-Holgersen 1996 Carr 1997 Watters 1997 Heslin 1997 Schilder 1998 Singh	30 32 31 60 28 28 164 94 43	SBT <24 hrs SBT<24 hrs SBT <24 hrs SBT <4 hrs^a SBT <2 hrs Jejun <2 hrs Jejun <24 hrs Oral intake <24h Jejun <12 hrs	19 vs. 14 15 vs. 10 18 vs. 16 12 vs. 8 9 vs. 10 16 vs. 17 — 4 vs. 3 13 vs. 15	5/15 vs. 3/15 0/16 vs. 1/16 8/17 vs. 3/14 14/30 vs. 2/30 3/14 vs. 0/14 - 6/83 vs. 6/81 — 22/22 vs. 8/21	— 7/16 vs. 3/16 — 5/30 vs. 6/30 13/14 vs. 3/14 3/15 vs. 3/13 23/83 vs. 31/81 — 7/22 vs. 8/21	— — — 4/30 vs. 2/30 1/14 vs. 0/14 - — — 4/22 vs. 4/21
Trauma 1984 Seri 1986 Moore 1998 Kompan	18 63 28	Jejun <12 hrs Jejun <24 hrs OG <6 hrs	— 29 vs. 25 14 vs. 11	2/8 vs. 1/10 9/31 vs. 3/32 —	— 15/31 vs. 14/32 MOF 3.1 vs. 2.5	— 2/31 vs. 1/32 —
Head injury 1989 Grahm 1999 Taylor	32 82	SBT <36 hrs OG/SBT<24 hrs	10 vs. 7^b —	14/15 vs. 3/17 35/41 vs. 25/41	__ 25/41 vs. 15/41	__ 6/41 vs. 5/41
Burns 1990 Chiarelli	20	<24 hrs	89 vs. 69	7/10 vs. 3/10^c	2/10 vs. 2/10	0/10 vs. 0/10

LOS, length of stay; SBT, small bowel tube; jejun, jejunostomy; MOF, multiple organ failure score.

^aDouble-blind, placebo-controlled randomized controlled trial.

^bIntensive care unit LOS.

^cPatients with bloodstream infection.

Author Conclusion:

The results of this meta-analysis support the experimental data demonstrating the benefit of the early initiation of enteral nutrition
The results of this meta-analysis must, however, be interpreted with some caution because of the significant heterogeneity between studies
This meta-analysis demonstrates a benefit of early enteral nutrition in reducing episodes of infection and LOS
It is noteworthy that the test for heterogeneity just reached statistical significance for infectious complications (P<0.049), whereas, it was highly significant for LOS (P<0.0012). This would suggest that the early initiation of enteral nutrition may directly impact on infectious complications, but that many other factors may determine LOS.
The results of our analysis of prospective, randomized clinical trials of early vs. delayed enteral nutritional support in critically ill patients indicate that early feeding decreases infectious complications and LOS
A large, multi-center, prospective, double-blind, randomized study would provide more definitive evaluation of the benefits of early enteral feeding
The studies in this report did not evaluate the use of gastric vs. small-bowel feeding tubes for early feeding
Additional studies addressing the site of feeding would be of clinical value.

Authors reported limitations:

Heterogeneity
Publication bias
Small sample sizes of studies
Types of nutritional formulas
Unable to control for risk
Could not meet inclusion criteria of critically ill patients
Did not evaluate the use of gastric vs. small-bowel feeding tubes for early feeding.

Funding Source:

University/Hospital:

The Mercy Hospital of Pittsburgh, Suburban Hospital

Reviewer Comments:

This is a very well written review and meta-analysis
The study inclusion is very well explained, however the exclusion criteria is very limited
This study provides support for early enteral feeding decreasing infectious complications and the LOS
Results are very well discussed with standard statistical appropriate analysis
I agree with the authors conclusion that a long term randomized trial is requried, but it is very difficult to run such a study. However, there are possibilities to conduct follow-up studies and regular case controlled studies. Very limited studies are currently available with very small number of subjects.
Further studies are needed to differentiate the condition, gender, age and other etiological factors need to be adjusted when doing the analysis
Overall, this metanalysis will provide an evidence that early enteral feeding is helpful to decrease infectious complications and the LOS.

Quality Criteria Checklist: Review Articles
Relevance Questions
	1.	Will the answer if true, have a direct bearing on the health of patients?	Yes
	2.	Is the outcome or topic something that patients/clients/population groups would care about?	Yes
	3.	Is the problem addressed in the review one that is relevant to dietetics practice?	Yes
	4.	Will the information, if true, require a change in practice?	Yes

Validity Questions
	1.	Was the question for the review clearly focused and appropriate?	Yes
	2.	Was the search strategy used to locate relevant studies comprehensive? Were the databases searched and the search termsused described?	Yes
	3.	Were explicit methods used to select studies to include in the review? Were inclusion/exclusion criteria specified andappropriate? Wereselectionmethods unbiased?	Yes
	4.	Was there an appraisal of the quality and validity of studies included in the review? Were appraisal methodsspecified,appropriate, andreproducible?	Yes
	5.	Were specific treatments/interventions/exposures described? Were treatments similar enough to be combined?	Yes
	6.	Was the outcome of interest clearly indicated? Were other potential harms and benefits considered?	Yes
	7.	Were processes for data abstraction, synthesis, and analysis described? Were they applied consistently acrossstudies and groups? Was thereappropriate use of qualitative and/or quantitative synthesis? Was variation in findings among studies analyzed? Were heterogeneity issued considered? If data from studies were aggregated for meta-analysis, was the procedure described?	Yes
	8.	Are the results clearly presented in narrative and/or quantitative terms? If summary statistics are used, are levels ofsignificance and/or confidence intervals included?	Yes
	9.	Are conclusions supported by results with biases and limitations taken into consideration? Are limitations ofthe review identified anddiscussed?	Yes
	10.	Was bias due to the review's funding or sponsorship unlikely?	???