Elke et al.

Critical Care (2016) 20:117

DOI 10.1186/s13054-016-1298-1

RESEARCH Open Access

Enteral versus parenteral nutrition in

critically ill patients: an updated systematic
review and meta-analysis of randomized
controlled trials
Gunnar Elke1, Arthur R. H. van Zanten2, Margot Lemieux3, Michele McCall4, Khursheed N. Jeejeebhoy5,
Matthias Kott1, Xuran Jiang3, Andrew G. Day3 and Daren K. Heyland3*

Abstract
Background: Enteral nutrition (EN) is recommended as the preferred route for early nutrition therapy in critically ill
adults over parenteral nutrition (PN). A recent large randomized controlled trial (RCT) showed no outcome differences
between the two routes. The objective of this systematic review was to evaluate the effect of the route of nutrition (EN
versus PN) on clinical outcomes of critically ill patients.
Methods: An electronic search from 1980 to 2016 was performed identifying relevant RCTs. Individual trial data were
abstracted and methodological quality of included trials scored independently by two reviewers. The primary outcome
was overall mortality and secondary outcomes included infectious complications, length of stay (LOS) and mechanical
ventilation. Subgroup analyses were performed to examine the treatment effect by dissimilar caloric intakes, year of
publication and trial methodology. We performed a test of asymmetry to assess for the presence of publication bias.
Results: A total of 18 RCTs studying 3347 patients met inclusion criteria. Median methodological score was 7 (range,
212). No effect on overall mortality was found (1.04, 95 % CI 0.82, 1.33, P = 0.75, heterogeneity I2 = 11 %). EN compared
to PN was associated with a significant reduction in infectious complications (RR 0.64, 95 % CI 0.48, 0.87, P = 0.004,
I2 = 47 %). This was more pronounced in the subgroup of RCTs where the PN group received significantly more
calories (RR 0.55, 95 % CI 0.37, 0.82, P = 0.003, I2 = 0 %), while no effect was seen in trials where EN and PN groups
had a similar caloric intake (RR 0.94, 95 % CI 0.80, 1.10, P = 0.44, I2 = 0 %; test for subgroup differences, P = 0.003).
Year of publication and methodological quality did not influence these findings; however, a publication bias may
be present as the test of asymmetry was significant (P = 0.003). EN was associated with significant reduction in ICU
LOS (weighted mean difference [WMD] -0.80, 95 % CI 1.23, 0.37, P = 0.0003, I2 = 0 %) while no significant
differences in hospital LOS and mechanical ventilation were observed.
Conclusions: In critically ill patients, the use of EN as compared to PN has no effect on overall mortality but
decreases infectious complications and ICU LOS. This may be explained by the benefit of reduced macronutrient
intake rather than the enteral route itself.
Keywords: Systematic review, Meta-analysis, Nutrition therapy, Enteral nutrition, Parenteral nutrition, Critically ill,
Intensive care unit, Infections, Randomized controlled trial

* Correspondence: [email protected]
3
Department of Critical Care Medicine, Queens University and Clinical
Evaluation Research Unit, Kingston General Hospital, Angada 4, K7L 2V7
Kingston, ON, Canada
Full list of author information is available at the end of the article

2016 Elke et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Elke et al. Critical Care (2016) 20:117 Page 2 of 14

Background and critically ill. The literature search was not confined
Artificial nutrition support has evolved into a primary to articles written only in English. The authors personal
therapeutic intervention to prevent metabolic deterior- files and reference lists of relevant review articles were
ation and loss of lean body mass with the aim to im- also reviewed. Neither ethics board approval nor patient
prove the outcome of critically ill patients. Apart from consent was required due to the nature of a systematic
the timing of initiation and the targeted amount of review.
macronutrients, the route of delivery is viewed as an
important determinant of the effect of the nutritional Study eligibility criteria
intervention. Using the enteral route is considered to Trials were included only if they met the following
be more physiologic, providing nutritional and various characteristics:
non-nutritional benefits including maintenance of
structural and functional gut integrity as well as pre- 1. Type of study: RCT with a parallel group.
serving intestinal microbial diversity [13]. The disad- 2. Population: critically ill adult patients (18 years of
vantage of enteral nutrition (EN) is related to a age), defined as patients admitted to an intensive
potential lower nutritional adequacy particularly in care unit (ICU). In the event that the information
the acute disease phase and in the presence of gastro- on the study population was unclear, we considered
intestinal dysfunction [4, 5]. In contrast, parenteral a mortality rate higher than 5 % in the control
nutrition (PN) may better secure the intended nutri- group to be consistent with critical illness. We
tional intake but is associated with more infectious excluded RCTs performed in elective surgery
complications, most likely due to hyperalimentation patients (such as cardiac surgery patients) even if
and hyperglycemia, as consistently shown in earlier patients were cared for in an ICU in the postoperative
meta-analyses [69]. These clinical data have trans- period.
lated into widespread consensus among current inter- 3. Intervention: enteral versus parenteral nutrition
national guideline recommendations [1013] and 4. Trial outcomes: the trial reported clinically relevant
expert opinions [14, 15] that the enteral route is pre- outcomes. Overall mortality was the primary
ferred in critically ill patients without a contraindica- outcome for this meta-analysis. Where available,
tion to EN. we extracted data regarding the primary mortality
Recently, Harvey and coworkers conducted the largest outcome reported as the principal outcome of the
randomized controlled trial (RCT) to date with respect study, including ICU, hospital, 28-day mortality or
to the effect of the route of nutrition on the outcome of other. Secondary outcomes were infections, ICU
critically ill adult patients [16]. In this pragmatic RCT and hospital length of stay (LOS), and duration of
involving 2388 patients, neither a significant difference mechanical ventilation with definitions of infections as
in mortality nor infectious complications was found be- defined in the original articles. As in previous meta-
tween the patients receiving total PN or EN within analyses conducted by our group, we excluded those
36 hours after admission and up to a maximum of 5 days. trials that reported only nutritional, biochemical,
These results have challenged the paradigm that EN is metabolic, or immunologic outcomes.
superior to PN with regard to clinical outcomes in crit-
ical illness. Data abstraction
Therefore, the objective of this study was to perform The methodological quality of the included trials was
an updated systematic literature review and meta- assessed in duplicate by two independent reviewers
analysis of this topic to evaluate the overall effect of the using a data abstraction form with a scoring system from
route of nutrition (EN versus PN) on clinical outcomes 0 to 14 according to the following criteria as previously
in adult critically ill patients. described [8, 17]:

Methods (a) the extent to which randomization was concealed,

Search strategy and study identification (b) blinding, (c) analysis based on the intention-to-treat
A literature review was conducted to identify all rele- (ITT) principle, (d) comparability of groups at baseline,
vant RCTs published between 1980 and January 2016 (e) extent of follow-up, (f ) description of treatment
in MEDLINE, Embase, CINAHL, the Cochrane Central protocol, (g) co-interventions, (h) definition of clinical
Register of Controlled Trials, and the Cochrane Database outcomes.
of Systematic Reviews. The following keywords or medical
subject headings were used: randomized, clinical trial, Disagreement concerning the individual score of each
nutrition support, artificial feeding, enteral nutrition, of the defined categories was resolved by consensus be-
parenteral nutrition, intensive care, critical illness, tween the two reviewers. Moreover, attempts were made
Elke et al. Critical Care (2016) 20:117 Page 3 of 14

to contact the authors of the included trials in order to Results

request further information not contained in the pub- Study identification and selection
lished article, if needed. The literature search identified 83 potentially eligible
randomized controlled trials, of which 65 were ex-
Statistical analysis cluded for the following reasons (see Table A1 in
Statistical analyses were performed using RevMan 5.3 Additional file 1): (a) patients not considered to be
(Cochrane IMS, Oxford, UK) with a random effects adult critically ill patients (N = 42), (b) no relevant
model. All trial data were combined to estimate the clinical outcomes meeting inclusion criteria reported
pooled risk ratio (RR) with 95 % confidence intervals (N = 4), (c) being duplicate studies, reviews of pub-
(CIs) for mortality and infections and overall weighted lished trials or subgroups of included studies (N = 11),
mean difference (WMD) with 95 % confidence intervals (d) non-randomized or pseudo-randomized study de-
for LOS and mechanical ventilation data. We calculated sign (N = 7), and/or (e) control group received a non-
pooled RRs using the Mantel-Haenszel estimator, and standard enteral formula (N = 1).
WMDs were estimated by the inverse variance approach. Thus, 18 RCTs with a total number of 3347 critically
The random effects model of DerSimonian and Laird ill adult patients were finally included in the meta-
was applied to estimate variances for the Mantel- analysis, whereof 1681 patients were treated with EN
Haenszel and inverse variance estimators [18]. In case and 1666 patients with PN.
RRs were undefined they were excluded for studies with The median methodological score of the included 18
no event in either arm. Heterogeneity testing was per- RCTs was 7 (range, 212) of which 10 RCTs were rated
formed using a weighted Mantel-Haenszel 2 test and with a score 7 and 8 RCTs with a score >7. The median
quantified by the heterogeneity I2 statistic as imple- year of publication was 19941995 with 10 RCTs pub-
mented in RevMan. Differences between subgroups were lished before or in 1995 and 8 RCTs after 1995. All
analyzed using the test of subgroup differences described results were based on the individual trial data shown in
by Deeks et al. [19], and the results expressed using the Tables 1 and 2.
P values.
Generating funnel plots and testing asymmetry of Effect of EN versus PN on mortality
outcomes using the method proposed by Rcker et al. Aggregating data from all studies reporting on mortality
[20] addressed possible publication bias. We consid- (N = 16) there was no difference in overall mortality be-
ered P < 0.05 to be statistically significant. tween the groups receiving EN or PN (RR 1.04, 95 % CI
0.82, 1.33, P = 0.75, heterogeneity I2 = 11 %) (Fig. 1). In
Subgroup analyses the subgroup analysis where trials were aggregated ac-
A predefined subgroup analysis was performed to fur- cording to the caloric intake across groups, no effect on
ther explore whether the treatment effect of either mortality was seen in trials (N = 4) where the PN group
route is associated with significant differences in the received significantly more calories than the EN group
caloric intake across the study groups (EN compared (RR 1.58, 95 % CI 0.75, 3.35, P = 0.23, heterogeneity
to PN). A priori, we hypothesized that a possible I2 = 48 %) or in the nine trials where the caloric in-
negative treatment effect of PN on mortality, infec- take was reported to be non-significantly different
tious complications and length of stay is related to a across groups (RR 1.03, 95 % CI 0.93, 1.14, P = 0.55,
higher caloric intake. We used the reported signifi- heterogeneity I2 = 0 %; test for subgroup differences:
cance level on caloric intake across groups from each P = 0.55) (Fig. 1, Panels a and b). Three RCTs did not
study to determine the allocation to the subgroup. report the caloric intake across study groups (Fig. 1,
We also assessed the effect of trial publication date Panel c). In the sensitivity analysis excluding two studies
and trial quality on the outcome based on the hy- [21, 22], there was still no difference in mortality between
pothesis that older or methodologically weaker studies groups (RR 1.08, 95 % CI 0.83, 1.39, P = 0.57, heterogen-
tended to yield a more negative treatment effect of eity I2 = 14 %).
PN. For this purpose, we designated trials with a pub-
lication date later than 1995 (median year 19941995) Effect of EN versus PN on infectious complications
as newer and trials with a methodological score of Eleven trials were aggregated which reported on infec-
more than 7 (median score) as methodologically stronger, tious complications. EN compared to PN was associated
respectively. In addition, we conducted a sensitivity ana- with a significant reduction in the incidence of infectious
lysis excluding two studies [21, 22] we were uncertain if complications (RR 0.64, 95 % CI 0.48, 0.87, P = 0.004,
the patients were truly critically ill [21] and about the trial heterogeneity I2 = 47 %; Fig. 2). The significant difference
results [22] and authors did not respond to attempts to was also seen in the subgroup analysis of five aggregated
obtain clarification. trials in which the PN group had a significantly higher
Elke et al. Critical Care (2016) 20:117 Page 4 of 14

Table 1 Included randomized controlled trials of enteral versus parenteral nutrition in critically ill patients
Author Year Population Setting Total patientsa EN group PN group Reference
Rapp et al. 1983 Head-injured patients Single-center 38 18 20 [37]
Adams et al. 1986 Critically ill trauma Single-center 46 23 23 [38]
Young et al. 1987 Brain-injured patients Single-center 51 28 23 [39]
Peterson et al. 1988 Critically ill patients with abdominal trauma Single-center 59 29 30 [40]
Cerra et al. 1988 Critically ill patients Single-center 70 33 37 [41]
Moore et al. 1989 Abdominal trauma Single-center 75 39 36 [42]
Kudsk et al. 1992 Abdominal trauma Single-center 98 52 46 [43]
Dunham et al. 1994 Blunt trauma Single-center 28b 12 16 [44]
Borzotta et al. 1994 Closed head injury Single-center 59 36 23 [45]
Hadfield et al. 1995 Mixed ICU medical-surgical Single-center 24 13 11 [46]
Kalfarentzos et al. 1997 Severe acute pancreatitis Single-center 38 18 20 [47]
Woodcock et al. 2001 ICU patients requiring nutrition support Single-center 38 17 21 [27]
Casas et al. 2007 Severe acute pancreatitis Single-center 22 11 11 [48]
Chen et al. 2011 Medical ICU Single-center 98b 49 49 [49]
Justo Meirelles et al. 2011 Traumatic brain injury Single-center 22 12 10 [21]
Wang et al. 2013 Surgical ICU (severe acute pancreatitis) Single-center 121b 61 60 [22]
Sun et al. 2013 Surgical ICU (severe acute pancreatitis) Single-center 60 30 30 [50]
Harvey et al. 2014 Mixed medical-surgical Multi-center 2400 1200 1200 [16]
EN enteral nutrition ICU intensive care unit PN parenteral nutrition
a
Total number includes number of ICU patients randomized in the trial, even if analysis was not according to intention-to-treat principle
b
Patients randomized to a third intervention group (combined enteral and parenteral nutrition) of the concerned trial were excluded from this meta-analysis

caloric intake than the EN group (RR 0.55, 95 % CI 0.37, significant difference was found between EN and PN
0.82, P = 0.003, heterogeneity I2 = 0 %) but not when the (WMD 0.67, 95 % CI 1.57, 0.24, P = 0.15, heterogeneity
five trials were aggregated where caloric intake was simi- I2 = 2 %; Fig. 3, Panel b). The non-significant difference
lar between EN and PN groups (RR 0.94, 95 % CI 0.80, remained in the subgroup analysis where trials were ag-
1,10, P = 0.44, heterogeneity I2 = 0 % [test for subgroup gregated according to the caloric intake across groups
differences: P = 0.003]) (Fig. 2, Panels a and b). One trial (RR 0.67, 95 % CI 1.57, 0.24, P = 0.15, heterogeneity
with data on infectious complications did not report the I2 = 2 %; test for subgroup differences: P = 0.08) (see
caloric intake across the EN and PN group (Fig. 2, Figure A2 in Additional file 2).
Panel c). EN compared to PN was still associated with
a significant reduction in infectious complications (RR Effect of EN versus PN on mechanical ventilation
0.58, 95 % CI 0.41, 0.8, P = 0.001, heterogeneity I2 = A total of four RCTs reported on length of mechanical
29 %) in the sensitivity analysis excluding the two ventilation (in mean and standard deviation) with no
studies with inconclusive status of critical illness [21, 22]. overall effect observed (WMD 0.38, 95 % CI 0.98,
0.21, P = 0.21, heterogeneity I2 = 0 %, Fig. 3, Panel c).
Effect of EN versus PN on ICU and hospital length of stay
Only four studies reported on ICU LOS (in mean and Effect of trial quality and publication date on outcomes
standard deviation [SD]) and when the data were aggre- and risk of publication bias
gated, the use of EN was associated with a significant re- According to the subgroup analyses, there was no effect
duction in ICU LOS (WMD 0.80, 95 % CI 1.23, 0.37, of either route of nutrition on overall mortality in high-
P = 0.0003, heterogeneity I2 = 0 %, Fig. 3, Panel a). In the quality trials (N = 7 RCTs; RR 1.05, 95 % CI 0.94,
subgroup analysis aggregating trials according to the cal- 1.16; P = 0.38, heterogeneity I2 = 0 %) compared to
oric intake across groups, the significant difference was not low-quality trials (N = 9 RCTs; RR 1.00, 95 % CI 0.62,
observed in the two trials where caloric intake was similar 1.60; P = 1.00, heterogeneity I2 = 30 %; test for sub-
between EN and PN groups (RR 0.47, 95 % CI 2.23, group differences: P = 0.85). This also applied to the
1,29, P = 0.60, heterogeneity I2 = 8 %) (see Figure A1 in comparison of older (N = 8 RCTS 1995; RR 1.01,
Additional file 2). A total of seven RCTs reported on hos- 95 % CI 0.56, 1.83; P = 0.98, heterogeneity I2 = 33 %)
pital LOS (with mean and standard deviation) where no versus more recent publications (N = 8 RCTs > year 1995;
 Elke et al. Critical Care (2016) 20:117
Table 2 Methodology and relevant outcome parameters of the included randomized clinical trials of enteral versus parenteral nutrition in critically ill patients
Study Methods (score) Mortality, N (%)a Infections, N (%)b LOS, days, mean SD (N) Mechanical ventilation, Caloric intakec
days, mean SD (N)
EN PN EN PN EN PN EN PN EN PN
1. Rapp et al. C.Random: 9/18 (50) 3/20 (15) NR Hospital 49.4d Hospital 52.6d 10.3d 10.4d 685 1750
1983 [37] not sure P = 0.001
ITT: no
Blinding: no (4)
2. Adams et al. C.Random: 1/23 (4) 3/23 (13) 15/23 (65) 17/23 (74) ICU 13 11 (19) ICU 10 10 (17) 12 11 (17) 10 10 (13) 2088 NSf 2572
1986 [38] not sure
ITT: yes Hospital 30 21 (19) Hospital 31 29
(17)
Blinding: no (8)
3. Young et al. C.Random: 10/28 (36) 10/23 (43) 5/28 (18) 4/23 (17) NR NR 1671 2299
1987 [39] not sure P = 0.02
ITT: no
Blinding: no (6)
4. Peterson et al. C.Random: NR 2/21 (10) 8/25 (32) ICU 3.7 0.8 (21) ICU 4.6 1.0 (25) NR Kcal on day 5
1988 [40] not sure
2204 2548
ITT: no Hospital 13.2 1.6 Hospital 14.6 1.9 P = 0.04
(21) (24)
Blinding: no (5)
5. Cerra et al. C.Random: ICU 7/31 (22) ICU 8/35 (23) NR NR NR Non-protein kcal
1988 [41] not sure
1684 NSf 2000
ITT: no
Blinding: no (2)
6. Moore et al. C.Random: yes NR 5/29 (17) 11/30 (37) NR NR Non-protein kcal
1989 [42] on day 5
ITT: no 1847 2261
P = 0.01
Blinding: no (10)
7. Kudsk et al. C.Random: ICU 1/51 (2) ICU 1/45 (2) 9/51 (16) 18/45 (40) Hospital 20.5 19.9 Hospital 19.6 18.8 2.8 4.9 (51) 3.2 6.7 (45) Kcal/kg/d
1992 [43] not sure (51) (45)
ITT: no 15.7 19.1
P < 0.05
Blinding:
single (10)
8. Dunham et al. C.Random: 1/12 (7) 1/15 (8) NR NR NR NSf
1994 [44] not sure
ITT: no
Blinding: no (8)

Page 5 of 14
 Elke et al. Critical Care (2016) 20:117
Table 2 Methodology and relevant outcome parameters of the included randomized clinical trials of enteral versus parenteral nutrition in critically ill patients (Continued)
9. Borzotta et al. C.Random: 5/28 (18) 1/21 (5) 51/28 (28) 39/21 (21) Hospitale 39 23.1 Hospitale 36.9 14 NR 2097 NSf 1961
1994 [45] not sure
ITT: no
Blinding: no (6)
10. Hadfield et al. C.Random: ICU 2/13 (15) ICU 6/11 (55) NR NR NR NSf
1995 [46] not sure
ITT: no
Blinding: no (7)
11. Kalfarentzos C.Random: ICU 1/18 (6) ICU 2/20 (10) 5/18 (28) 0/20 (50) ICU 11 (521)d ICU 12 (524)d 15 (616)d 11 (731)d Non-protein
et al. 1997 [47] not sure kcal/kg/d
ITT: no Hospital 40 (2583)d Hospital 39 (2273)d 24.1 NSf 24.5
Blinding:
single (9)
12. Woodcock C.Random: yes 9/17 (53) 5/21 (24) 6/16 (38) 11/21 (52) 33.2 43 (16) 27.3 18.7 (18) NR % caloric target
et al. 2001 [27] (30 kcal/kg/d)
achieved
ITT: yes 54.1 96.7
P < 0.001
Blinding:
single (12)
13. Casas et al. C.Random: Hospital 0/11 (0) Hospital 2/11 (18) 1/11 (9) 3/11 (27) Hospital 30.2 Hospital 30.7 NR Kcal/kg/d
2007 [48] no/unsure (average) (average)
ITT: Yes 20.1 NSf 20.8
Blinding: no (8)
14. Chen et al. C.Random: yes 20-day 11/49 (22) 20-day 10/49 (20) 5/49 (10) 18/49 (37) ICU 9.09 2.75 ICU 9.60 3.06 7.95 2.11 8.23 2.42 NR
2011 [49]
ITT: yes
Blinding: no (7) Hospital 23.32 5.6 Hospital 22.24 3.27
15. Justo Meirelles C.Random: no Not specified Not specified 1/10 Total infectious Total infectious ICU 14 (526) ICU 14 (624) NR Cumulative kcal
et al. 2011 [21] 1/12 (8.3) (10) complications complications over 5d
2/12 (16.7) 4/10 (40)
ITT: no Pneumonia Pneumonia 5985 6586
2/12 (16.7) 2/10 (20) P = 0.34
Blinding: no (5) Sepsis 0 Sepsis 2/10 (20)
16. Wang et al. C.Random: no Hospital 3/61 (5) Hospital 7/60 (12) Pancreatic sepsis Pancreatic sepsis NR NR NR
2013 [22] 13/61 (21) 24/60 (40)
ITT: no
Blinding: MODS 15/61 MODS 22/60 (36.7)
double (7) (24.6)
17. Sun et al. C.Random: no Hospital 2/30 (7) Hospital 1/30 (3) Pancreatic 3/30 Pancreatic 10/30 (33) ICU 9 (514) ICU 12 (821) NR NR

Page 6 of 14
2013 [50] (10)
ITT: no MODS 5/30 (17) MODS 13/30 (43)
Blinding: no (6) SIRS 12/30 (40) SIRS 22/30 (73)
 Elke et al. Critical Care (2016) 20:117
Table 2 Methodology and relevant outcome parameters of the included randomized clinical trials of enteral versus parenteral nutrition in critically ill patients (Continued)
18. Harvey et al. C.Random: yes ICU 352/1197 ICU 317/1190 Total infectious Total infectious ICU 11.3 12.5 ICU 12 13.5 8.2 9.3 8.7 11.5 Cumulative kcal/
2014 [16] (29.4) (26.6) complications complications (1197) (1190) (1197) (1189) kg/d over 5d
194/1197 (16.2)g 194/1191 (16.3)g
ITT: yes Hospital 450/1186 Hospital 431/1185 Pneumonia Pneumonia Hospital 26.8 33.2 Hospital 27.5 33.9 74 NSf 89
(37.9) (36.4) 143/1197 (11.9) 135/1191 (11.3) (1186) (1185)
30-day 409/1195 30-day 393/1188 Bloodstream Bloodstream
(34.2) (33.1) infections infections
21/1197 (1.8) 27/1191 (2.9)
Blinding: 90-day 464/1188 90-day 442/1184 Surgical infections Surgical infections
no (8) (39.1) (37.3) 12/1197 (1.0) 10/1191 (0.8)
Data are presented as total number and percentage for mortality and infections. Data are presented as mean standard deviation with total number of patients per group shown in brackets for LOS and
mechanical ventilation
C.Random concealed randomization, d days, ITT intention to treat, kcal kilocalories, LOS length of stay, MODS multiple organ dysfunction syndrome, N number, NR not reported, NS not significant, SIRS systemic
inflammatory response syndrome
a
Presumed hospital mortality unless otherwise specified
b
Refers to the number of patients with infections unless otherwise specified
c
Caloric intake is presented as the mean daily kcal during the studies intervention period or as otherwise specified
d
Median/mean values, no standard deviation reported hence not included in meta-analysis
e
Presumed hospital length of stay
f
No data on caloric intake or P value provided, respectively but caloric intake reported to be non-significantly different in the manuscript
g
Data on ICU patients obtained directly from authors

Page 7 of 14
Elke et al. Critical Care (2016) 20:117 Page 8 of 14

Fig. 1 Effects on overall mortality in studies comparing enteral versus parenteral nutrition (N = 16 studies). Panel a shows the subgroup of
aggregated trials in which the caloric intake in the PN group was significantly higher than in the EN group, Panel b shows the subgroup of
aggregated trials in which the PN and EN groups received similar caloric intake, and Panel c includes the trials where caloric intake was not
reported. CI confidence interval, EN enteral nutrition, M-H Mantel-Haenszel test, PN parenteral nutrition

RR 1.05; 95 % CI 0.94, 1.16; P = 0.38, heterogeneity and independent of the trial publication date (N = 6
I2 = 0 %; test for subgroup differences: P = 0.90). With RCTs > 1995; RR 0.61; 95 % CI 0.37, 0.99; P = 0.05, hetero-
respect to infectious complications, the positive treatment geneity I2 = 55 % and N = 5 RCTs 1995; RR 0.62; 95 % CI
effect of EN remained significantly independent of meth- 0.39, 0.98; P = 0.04, heterogeneity I2 = 39 %; test for sub-
odological trial quality (N = 4 RCTs with score 7; RR group differences: P = 0.94) (see Figure A4 in Additional
0.42; 95 % CI 0.23, 0.77; P = 0.005; heterogeneity I2 = 6 % file 4). Results regarding the treatment effect of EN versus
and N = 7 RCTs with score > 7; RR 0.76; 95 % CI 0.58, PN on ICU and hospital LOS in both subgroup analyses
0.99; P = 0.04; heterogeneity I2 = 37 %; test for subgroup also remained concordant compared with the primary
differences: P = 0.08) (see Figure A3 in Additional file 3) analyses. Funnel plots for all outcome measures were
Elke et al. Critical Care (2016) 20:117 Page 9 of 14

Fig. 2 Effects on infectious complications in studies comparing enteral versus parenteral nutrition (N = 11 studies). Panel a shows the subgroup of
aggregated trials in which the caloric intake in the PN group was significantly higher than in the EN group, Panel b shows the subgroup of
aggregated trials in which the PN and EN groups received similar caloric intake, and Panel c includes one trial where caloric intake was not
reported. CI confidence interval, EN enteral nutrition, M-H Mantel-Haenszel test, PN parenteral nutrition

created to further test for potential publication bias. The nutrition. EN as compared to PN led to a significant re-
test for asymmetry was found to be significant for the re- duction in the number of infectious complications and
ported endpoint infectious complications (P = 0.003) ICU LOS while no significant effect was found with
(Fig. 4). No significant differences were found with respect respect to hospital LOS and mechanical ventilation.
to the remaining endpoints of overall mortality (P = 0.61), However, the positive treatment effect of EN on infec-
ICU LOS (P = 0.34), hospital LOS (P = 0.30) or mechanical tious morbidity and ICU LOS may be attributed to
ventilation (P = 0.65) (data not shown). differences in caloric intake between study groups. Fur-
thermore, funnel plot analysis revealed evidence for
Discussion significant publication bias for the trials reporting on in-
This updated meta-analysis on the effect of the route of fectious complications.
nutrition (EN versus PN) on clinical outcomes included
18 randomized controlled trials with a total of 3347 ran- Comparison to other meta-analyses
domized critically ill adult patients. Overall, there was Six previous meta-analyses comparing the effect of EN
no difference in mortality between the two routes of versus PN on clinical outcomes of critically ill adults
Elke et al. Critical Care (2016) 20:117 Page 10 of 14

Fig. 3 Effects on length of stay and mechanical ventilation in studies comparing enteral versus parenteral nutrition. Panel a shows aggregated
trials with information on ICU length of stay, Panel b shows aggregated trials with information on hospital length of stay. Panel c shows
aggregated trials with information on length of mechanical ventilation (in mean and standard deviation). CI confidence interval, EN enteral
nutrition, ICU intensive care unit, IV inverse variance, LOS length of stay, M-H Mantel-Haenszel test, PN parenteral nutrition, SD standard deviation

reported no significant overall difference in mortality be- duration of 5 days after ICU admission. The calorie and
tween the two routes of nutrition [6, 7, 9, 2325]. The protein intake was similar, albeit low with respect to the
meta-analysis by Simpson and Doig [25] including 11 predefined nutrition target in both groups, while initi-
RCTs only showed a mortality benefit of PN in a prede- ation of oral feeding was allowed if clinically indicated
fined subgroup analysis where PN was compared to during the intervention period. Neither were there sig-
delayed EN (odds ratio [OR] 0.29, 95 % CI 0.12, nificant differences in the 90-day mortality primary end-
0.70, P = 0.006; heterogeneity I2 = 0 %, statistical het- point nor in the rate of infectious complications or other
erogeneity P = 0.60). In the absence of an overall secondary outcome measures including LOS variables
mortality effect, all of these meta-analyses showed and duration of mechanical ventilation. Why the in-
significant reductions in the rate of infectious com- creased infectious morbidity seen with PN in the former
plications with the use of EN and one meta-analysis trials and meta-analyses was not observed in this latest
also showing a significant reduction of hospital LOS largest RCT may have been related to the equally hypo-
(WMD = 1.20 days; 95 % CI 0.38, 2.03; P = 0.004) [9]. caloric delivery of macronutrients via both routes.
In contrast to these previous meta-analyses, our up-
dated results include the data of the recent multicenter Effect of dissimilar caloric intake
RCT (Calories trial) by Harvey and coworkers [16]. In In contrast to the results of the Calories trial [16], the
this pragmatic trial including 2400 critically ill patients, overall significant positive treatment effect of EN on
the use of total PN was compared with EN for a infectious morbidity and ICU LOS remained in our
Elke et al. Critical Care (2016) 20:117 Page 11 of 14

0.0
0.20.4
Standard error
0.6 0.8
1.0

0.1 0.2 0.5 1.0 2.0 5.0

Risk Ratio
Fig. 4 Funnel plot for 11 RCTs reporting the endpoint infectious complications. Test for asymmetry P = 0.003

updated meta-analysis. On the one hand, this overall metabolic control [28]. Caloric overfeeding per se is
treatment effect may reflect the positive non-nutritional regarded to negatively influence outcomes with an in-
effects of EN in terms of preservation of gut integrity creased risk of infectious complications while a re-
and intestinal microbial diversity as well as promotion of stricted delivery of macronutrients or the avoidance of
gut-mediated immunity, all of which may support the overfeeding may preserve autophagy and thus likely
systemic immune response [2, 26]. Presumably, the dur- positively influence outcome [29, 30]. Unfortunately,
ation of the intervention (5 days) in the Calories trial owing to the limited number of trials in which the rela-
[16] was likely too short or not intense enough in a tion of nutritional intakes and predefined targets were
population with a mortality rate of 34 % that the benefi- reported, we were neither able to further explore the
cial non-nutritional, trophic effects of EN became evi- treatment effect of nutritional adequacy nor hypergly-
dent with respect to infectious morbidity and ICU LOS. cemia on infectious complications in more detail. With
On the other hand, our subgroup findings support the respect to the effect of EN-specific complications such
hypothesis that not the route per se but rather likely the as vomiting, aspiration or diarrhea on clinical outcomes,
dissimilar amount of calories delivered may have influ- we were unable to complete another subgroup analysis
enced the treatment effect on infectious complications. due to inconsistent reporting in the included RCTs.
While there was a significant treatment effect difference The Calories trial revealed that PN as compared to
in the subgroup of five RCTs where caloric intake was EN was associated with a lower rate of vomiting and
reported to be significantly higher in the PN group, no diarrhea but a higher rate of constipation [16]. How-
treatment effect on infectious complications was ob- ever, the impact of EN-specific complications remains
served in the five trials with similar caloric intake across inconclusive given the non-significant differences in
the study groups. This latter subgroup observation was major clinical outcomes in the Calories trial and two
largely driven by the Calories trial contributing 23.8 % of other large RCTs comparing the effect of different EN
the overall estimate [16]. Furthermore, studies showing feeding strategies [31, 32].
differences in infectious complications were associated
with publication bias. Except for one RCT [27], the cal- Effect of trial quality and publication bias
oric intake in the PN group was gradually increased to Most of the RCTs that were aggregated in our meta-
target in all aggregated trials. Still, PN as compared to analysis were single-center trials reporting small total
EN poses a higher risk of providing macronutrients in number of patients, and ten RCTs were published more
excess of the metabolic capacity, particularly in the early than 20 years ago. Based on the hypothesis that older or
phase of illness and in the absence of appropriate methodologically weaker studies per se tended to yield
Elke et al. Critical Care (2016) 20:117 Page 12 of 14

the more negative treatment effect of PN, we performed reported data in the trials. It is likely that EN will incur
additional subgroup analyses as well as funnel plots to less cost as compared to PN as shown by a secondary
assess risk of publication bias. In the early meta-analysis analysis of the Calories trial [36].
by Braunschweig et al., the positive treatment effect of
EN compared to PN on infection rates was independent Conclusions
of the publication date and trial quality score [6]. While In this comprehensive and most up-to-date systematic
the positive treatment effect of EN on infectious morbid- review we found that the route of nutrition (EN versus
ity accordingly appeared to be independent of the publi- PN) does not impact mortality in a heterogeneous popu-
cation date and methodological trial quality in our meta- lation of critically ill adult patients. Overall, the use of
analysis, the funnel plot analysis revealed significant EN as compared to PN significantly reduced the rate of
asymmetry with respect to infectious complication rates. infectious complications and length of ICU stay. How-
This bias is apparently driven by the published smaller ever, the different treatment effect concerning infectious
trials showing a larger treatment effect weakening the morbidity favouring EN must be interpreted in light of
strength of the inference we can make about the overall the observed differences in caloric intake across study
effect of the route of nutrition on infectious complica- groups and publication bias of included trials. Although
tion rates. these observations reduce the strength of inference with
respect to the negative effects of PN on infectious mor-
Strength and limitations bidity, the observed favourable effects of EN on ICU
The strengths of our meta-analysis are the comprehen- LOS, the ease of access, and lower costs in patients who
sive and most up-to-date search of the worldwide litera- tolerate EN should be considered. Therefore, in accord-
ture without restriction to only English-written articles, ance with the most recent guideline recommendations
the inclusion of data from the largest and most recent [11, 12], we posit that EN still should be considered the
RCT by Harvey and coworkers [16], the duplicate data first-line nutritional therapy in adult critically ill patients
abstraction and specific criteria for searching and ana- with a functioning gastrointestinal tract.
lysis, and the analysis of trial quality, publication year,
and publication bias. Limitations of our meta-analysis
Key messages
include the missing outcome data points in some of the
included trials, and the small number of aggregated trials
 This updated meta-analysis on effects of EN versus
with data on the clinical endpoints ICU LOS and dur-
PN on clinical outcomes included 18 RCTs with
ation of mechanical ventilation. Further limitations are
3347 randomized critically ill patients
the variation in reporting the caloric intake, the time of
 There was no significant difference in mortality
nutrition intervention, and the definitions used for infec-
between patients fed via EN or PN
tions with or without adjudication across the trials in-
 Compared to PN, the use of EN was associated with
cluded in the subgroup analysis. We were also unable to
a significant reduction of infectious complications
separate the effect of protein intake via both routes on
and ICU LOS
the reported clinical endpoints among the included
 This positive treatment effect of EN compared to
trials. Thus, there may be other covariates driving the
PN may be attributed to differences in caloric intake
observed findings that were not adjusted for in our
and significant publication bias among aggregated
meta-analysis. This may also pertain to possible treat-
trials
ment effect differences of EN versus PN among specific
 EN still should be considered first-line nutritional
subpopulations of critically ill patients, such as those
therapy over PN in critically ill patients with a
with a different nutritional risk upon ICU admission.
functioning gastrointestinal tract
The results of our meta-analysis may not be applicable
to patients with a relative short-term or absolute contra-
indication for EN where the treatment effect of PN (as Additional files
compared to standard care or no nutrition) on clinical
Additional file 1: Table A1. Excluded studies of enteral versus
outcomes may differ, as shown in two recent large RCTs parenteral nutrition. (PDF 109 kb)
[33, 34]. Moreover, the effect on long-term functional Additional file 2: Figure A1. Subgroup analysis comparing the effect
outcomes were not studied in the aggregated RCTs but of enteral versus parenteral nutrition according to the caloric intake
are currently viewed as the more appropriate endpoints on length of intensive care unit stay (N = 4 studies). Panel A shows
the subgroup of aggregated trials in which the caloric intake in the
to be influenced by different nutritional interventions in- PN group was significantly higher than in the EN group, Panel B
cluding the route and amount of nutrition [14, 35]. shows the subgroup of aggregated trials in which the PN and EN
Lastly, we did not examine cost-effectiveness of the two groups received similar caloric intake and Panel C including one trial
where caloric intake was not reported. CI confidence interval, EN
strategies of nutrition due to the inconsistency of
Elke et al. Critical Care (2016) 20:117 Page 13 of 14

enteral nutrition, M-H Mantel-Haenszel test, PN parenteral nutrition. Kingston General Hospital, Angada 4, K7L 2V7 Kingston, ON, Canada.
4
Figure A2. Subgroup analysis comparing the effect of enteral versus Medical/Surgical ICU, Specialized Complex Care, St Michaels Hospital, 30
parenteral nutrition on length of hospital stay according to the caloric intake Bond Street, Toronto, ON, Canada. 5Department of Nutritional Sciences, St
(N = 7 studies). Panel A shows the subgroup of aggregated trials in which Michaels Hospital, 30 Bond Street, Toronto, ON, Canada.
the caloric intake in the PN group was significantly higher than in the EN
group, Panel B shows the subgroup of aggregated trials in which the PN Received: 2 March 2016 Accepted: 14 April 2016
and EN groups received similar caloric intake and Panel C including one trial
where caloric intake was not reported. CI confidence interval, EN enteral
nutrition, IV inverse variance, M-H Mantel-Haenszel test, PN parenteral
nutrition. (PDF 148 kb) References
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