Clinical Nutrition 40 (2021) 3940e3949

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Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Meta-analyses

Association of specialized enteral nutrition with glycemic control and

clinical outcomes in critically ill patients: A meta-analysis of
randomized controlled trials

via M. Silva c, *, Jussara C. de Almeida b, d, e
Igor Eckert a, Magali C.C. Kumbier b, Fla
a
Nutrition Undergraduate Program, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rio Grande do Sul, Brazil
b
Graduate Program on Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rio Grande do Sul,
Brazil
c
Department of Nutrition and Postgraduate Program in Nutrition Sciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rio Grande do
Sul, Brazil
d
Division of Nutrition and Dietetics, Hospital de Clínicas de Porto Alegre (HCPA), Rio Grande do Sul, Brazil
e
Department of Nutrition, Faculdade de Medicina, Universidade Federal Do Rio Grande Do Sul, Rio Grande do Sul (UFRGS), Brazil

a r t i c l e i n f o s u m m a r y

Article history: Objective: To evaluate the association of glycemic-control formulae (GCF) with measurements of gly-
Received 2 February 2021 cemic control and clinical outcomes compared to standard enteral formulae (SF) in critically ill patients.
Accepted 19 April 2021 Data sources: MEDLINE, EMBASE, Scopus and the Cochrane Central Register of Controlled Trials were
searched from inception up to January, 2021.
Keywords: Study selection: RCTs that assessed the effects of GCF relative to SF in adult critically ill patients.
Nutrition therapy
Data extraction: Measurements of glycemic control were the primary outcomes. Secondary outcomes
Critical illness
included insulin requirements, mechanical ventilation (MV), length of intensive care unit (ICU) stay and
Hyperglycemia
Meta-analysis
mortality. Two authors independently extracted data and assessed risk of bias using the Cochrane's RoB 2
Enteral feeding tool and the GRADE approach was used to assess the quality of evidence.
Glycemic variability Data synthesis: Ten studies (12 reports, 685 patients) were included. The use of GCFs was associated with
lower blood glucose (WMD,
16.06 mg/dL; 95% CI -23.48 to
8.63; I2 ¼ 47%) and lower daily admin-
istered insulin (WMD,
7.20 IU; 95% CI -13.92 to
0.48; I2 ¼ 53%). Glycemic variability, measured by the
coefficient of variation, was also associated with the use of GCFs (WMD,
6.84%; 95% CI,
13.57 to
0.11;
I2 ¼ 95%). In contrast, analyses for length of ICU stay (WMD,
0.12, 95% CI -1.77 to 1.52; I2 ¼ 0%), duration
of MV (WMD,
0.34 days; 95% CI,
1.72 to 1.04; I2 ¼ 0%) and mortality (RR, 1.13; 95% CI 0.82 to 1.56;
I2 ¼ 0%) were not statistically significant. Quality of evidence ranged from low to very low, and only one
study was judged as at low risk of bias.
Conclusions: In this meta-analysis, GCFs were significantly associated with lower insulin requirements
and improved glycemic control. Although results for clinical outcomes were not statistically significant,
there is insufficient evidence to confirm or exclude important differences due to serious imprecision in
the effect estimates and overall low quality of evidence. The effects of GCFs on clinical outcomes require
confirmation in larger randomized trials.
© 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction

Stress-induced hyperglycemia is a byproduct of a systemic in-

* Corresponding author. Department of Nutrition and Postgraduate Program in
Nutrition Sciences, Federal University of Health Sciences of Porto Alegre, Sarmento

rico, Porto Alegre, Rio Grande do Sul, 90050-170, Brazil.
Leite St., 245, Centro Histo
E-mail address: flaviams@ufcspa.edu.br (F.M. Silva).
flammatory state caused by metabolic responses to infections, in-
juries and illnesses [1]. Impaired glucose homeostasis is of common
occurrence in the critically ill, affecting as many as 75% of the pa-
tients [2,3]. Consistent evidence supports optimization of blood
glucose levels as a means to improve clinical outcomes [4e6] in

https://doi.org/10.1016/j.clnu.2021.04.030
0261-5614/© 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
I. Eckert, M.C.C. Kumbier, F.M. Silva et al.
patients receiving insulin therapy for persistent hyperglycemia [7].
Glycemic disorders are however not limited to sustained hyper-
glycemia, as mounting evidence suggests that the glycemic vari-
ability (defined as fluctuations of blood glucose by amplitude,
frequency and duration) is also independently associated with
increased mortality risk [8,9] and intensive care unit (ICU)-acquired
infections [10].
Critically ill patients are often prescribed early enteral feeds as
this has been associated with reductions in mortality and infectious
morbidity [11,12] but the provision of carbohydrates itself might
amplify blood glucose excursions and exacerbate its variability.
Insulin infusion is an effective, longstanding first-class therapy for
glucose control; however, there are inherently associated risks of
hypoglycemia which may also lead to increased mortality risk [13].
In this sense, specialized nutrition therapy could be beneficial by
lowering glucose levels and insulin requirements, as well as
attenuating glycemic fluctuations [14]. Disease-specific formulae
were developed to enhance glycemic control, typically with a lower
carbohydrate content (and/or low glycemic index) and added fiber,
as well as a higher proportion of total fat and/or monounsaturated
fatty acids (MUFAs). Systematic reviews have shown significant
improvements of glycemic control with specialized formulae (as
oral supplements and/or enteral feeds) in hospitalized patients
with diabetes in comparison to standard formulae (SF) [15,16].
However, studies performed in acute-care settings were either not
included [17] or not analyzed in isolation [18] in past reviews.
Due to the lack of evidence whether the selection of specialized
glycemic-control enteral formulae (GCF) is associated with bene-
ficial effects in critically ill patients, international guidelines have
recommended the use of standard polymeric enteral feeds even in
the presence of persistent stress-induced hyperglycemia
[7,11,19e21]. To fill the knowledge gap regarding the role of
specialized enteral nutrition therapy, the current systematic review
aimed to evaluate the effects of GCFs on glycemic control and
clinical outcomes in adult and elderly critically ill patients and
further assess whether current evidence is conclusive by a trial
sequential analysis.
2. Methods
2.1. Design and protocol
This study is a systematic review and meta-analysis conducted
according to the Cochrane Handbook for Systematic Reviews of
Interventions [22] and pre-registered in PROSPERO (CRD:
42,016,036,495). Reporting was consistent with the PRISMA
guidelines [23].
2.2. Eligibility criteria
Records that met the Patient, Intervention, Comparators,
Outcome and Study Design (PICOS) criteria were deemed eligible
for inclusion (Table 1). We in aimed to include studies of the
Table 1
PICOS criteria used for inclusion and exclusion of studies.
Parameter Description
Participants Adult or elderly critically ill patients admitted to an ICU
Intervention(s) Enteral glycemic-control formulae
Comparison(s) Standard enteral formulae
Outcome(s) Primary outcomes: measurements of glycemic control. Secondary outcomes:
insulin requirements and clinical outcomes (mortality, ICU length of stay and duration of mechanical ventilation)
Study design Randomized controlled trials of cross-over or parallel design
Abbreviations: ICU, intensive care unit.
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Clinical Nutrition 40 (2021) 3940e3949
following characteristics: (1) RCTs that reported at least one mea-
surement of glycemic control as an outcome; (2) population of
interest was composed of adults (age 18 years) admitted to an
ICU; (3) an enteral glycemic-control formulae (GCF) was the
intervention under investigation and (4) the control group was
assigned to receive a standard formulae (SF). Enteral GCFs were
defined as formulae matching at least one of the following char-
acteristics, relative to SFs: lower carbohydrate content; carbohy-
drates with lower glycemic index (e.g., fructose); greater amounts
of dietetic fiber; and/or higher proportions of total or mono-
unsaturated fatty acids [17]. Glycemic control was chosen as our
primary outcome of interest because assessing surrogate outcomes
is more feasible than assessing clinical outcomes such as mortality
with regards to recruiting enough participants for an acceptable
level of statistical power. For this reason, we assumed that there
would not be many interventional studies investigating the effects
of GCFs on clinical outcomes and decided to focus on glycemic
control as our primary measurement of interest. In addition, it is
reasonable to assume that if there is an effect of GCFs on clinical
outcomes, the most likely explanation for an effect would be
through improved glycemic control and/or lower insulin re-
quirements as the causal intermediates, which further compounds
to our choice of primary outcome. Furthermore, although ran-
domized controlled trials of cross-over design are not suitable to
address irreversible clinical outcomes in the ICU, we have decided
to include cross-over studies as long as they have reported any
measurement of glycemic control and/or insulin requirements.
Studies were excluded if enteral nutrition was associated with
or compared to either oral or parenteral nutrition therapy, due to
different glycemic responses associated with incretin-mediated
endogenous insulin release [24]. Unpublished studies with no
full-text available were also not included.
2.3. Search strategy
A comprehensive search was was developed and performed by
I.E. and F.M.S. in MEDLINE, EMBASE, Scopus, and the Cochrane
Central Register of Controlled Trials from inception to July 2020,
with no restrictions to language or date. The search was updated in
January 2021. Search strategy consisted of several variations of
terms related to enteral nutrition (intervention), critically ill and
intensive care (participants), glycemic control (outcomes) and RCTs
(study design). We have employed sensitivity-maximizing search
filters for identifying RCTs in PubMed and EMBASE according to
Cochrane recommendations [22]. The complete search strategy for
each database is available in Table S1 (Supporting Information
Online). Reference lists of included studies were also manually
screened. Sources of grey literature were clinical trial registries
(ClinicalTrials.gov), OpenGrey and abstracts of European Society for
Clinical Nutrition and Metabolism (ESPEN), American Society of
Parenteral and Enteral Nutrition (ASPEN) and International Sym-
posium of Intensive Care and Emergency Medicine (ISICEM) sci-
entific meetings of the last five years.
I. Eckert, M.C.C. Kumbier, F.M. Silva et al.
2.4. Study selection
The retrieved studies were imported to a bibliography man-
agement software (EndNote®) and duplicates were excluded. The
first stage of study selection was independently performed by two
researchers (I.E. and F.M.S.) by screening titles and abstracts and
any disagreements were resolved by consensus. In the second
stage, the full-text of selected studies were independently exam-
ined by two investigators (I.E. and M.K.) using a standardised
electronic eligibility form based on our pre-specified PICOS criteria.
Records that did not meet the eligibility criteria were excluded. At
this stage, disagreements were resolved along with a third inves-
tigator (F.M.S.).
2.5. Data extraction process
Data from included studies were independently extracted to
Microsoft Word® tables by two reviewers (I.E. and M.K.) using a
standardized electronic form and subsequently crosschecked with
a third investigator (F.M.S.). Data included information about study
design and follow-up duration; characteristics of participants and
interventions; attrition rates and outcomes of interest (measures of
glycemic control as the primary outcomes; insulin requirements,
mortality, length of ICU stay and mechanical ventilation as sec-
ondary outcomes).
We have attempted to contact study authors for unreported or
unclear information. Missing standard deviations were handled
using Ma's et al. [25] prognostic imputation method, predicting
missing standard errors from included trials with known data.
2.6. Assessment of risk of bias and quality of evidence
Two reviewers (I.E. and F.M.S.) independently assessed risk of
bias of each trial using Cochrane's RoB 2 tool, and disagreements
were solved by consensus [26]. Each domain was classified as ‘low
risk of bias’, ‘some concerns’ or ‘high risk of bias’. The overall quality
of evidence was assessed using the Grading of Recommendations
Assessment, Development and Evaluation (GRADE) approach to
evaluate factors that may decrease confidence in estimates of effect
for each individual outcome across studies. Each outcome was
associated with a ‘high’, ‘moderate’, ‘low’, or ‘very low’ quality of
evidence [27].
2.7. Data synthesis and statistical analysis
Changes in continuous outcomes were reported as the
weighted mean difference (WMD) between treatment groups
with 95% CIs assuming an inverse variance model. Dichotomous
outcomes were analyzed using the Mantel-Haenszel statistical
method and reported as relative risk with 95% CIs. Data were
pooled assuming a random effects model for all analyses. Signif-
icance level was set to p < 0.05. Crossover and parallel trials were
combined if 1) they estimated the same treatment effect and 2)
there were no differences in therapeutic indication that could
influence the observed treatment effect on the basis of design
selection [28]. All analyses were conducted using statistical
packages implemented in R version 3.6.2 (R Project for Statistical
Computing). In clinical trials with two or more intervention
groups compared to a single control group, we have decided to
split each study into two reports, which were renamed with an
additional (a) and (b) marker for clarity. This decision was based
on recommendations in chapter 16.5.4 of the Cochrane Handbook,
which states that in order to overcome the issue of unit-of-anal-
ysis error it is possible to split the ‘shared’ group (i.e., the control
group using standard enteral formulae) into two groups with
3942
Clinical Nutrition 40 (2021) 3940e3949
smaller sample size, and include two (reasonably independent)
comparisons. For dichotomous outcomes, both the number of
events and the total number of patients of the control group were
divided up; for continuous outcomes, only the total number of
participants of the control group was divided up and the means
and standard deviations were left unchanged.
2.8. Assessment of heterogeneity, publication bias and subgroup
analysis
The presence of between-study heterogeneity was evaluated
using Cochran's Q test with p < 0.10 considered for statistical sig-
nificance along with the I2 method to evaluate the magnitude of
heterogeneity. Exploratory analyses were performed through sub-
groups of (a) studies including patients with diabetes, because the
benefit of GCFs might be greater in this population [29,30]; (b)
studies of patients with higher baseline glucose levels [31,32], with
a cut-off point set at 180 mg/dL representing uncontrolled hyper-
glycemia [7]; and (c) risk of bias categories (low risk of bias versus
some concerns/high risk of bias). We performed sensitivity analyses
for the primary outcome excluding studies with crossover design
and studies that measured plasma glucose instead of capillary
glucose. Finally, we employed Egger's regression along with visual
inspection of funnel plots to assess potential risk of publication bias
for outcomes with a minimum of 10 pooled reports.
2.9. Trial sequential analysis
In order to assess whether our meta-analysis was sufficiently
powered to support definitive conclusions, we performed a trial
sequential analysis (TSA) [33,34]. We set the TSA with an overall
5% risk of type I error and 20% risk of type II error and calculated
the required information size using the O'Brien-Fleming
approach for blood glucose levels, insulin requirements, glucose
coefficient of variation and mortality using the TSA software
0.9.5.10 Beta.
3. Results
3.1. Study selection and characteristics
There were 1621 studies identified in the initial search, of which
1037 were screened after exclusion of duplicate records. A total of
16 studies underwent full-text examination and 10 [35
44] were
included in the current work. The selection process is displayed in
Fig. 1.
Clinical and methodological characteristics of the selected
studies are shown in Table 2, totaling 685 randomized patients with
a mean age of 59.2 years, of which 65.68% were male. Mean BMI
ranged from 22.6 to 33.4 kg/m2 (data not reported in three studies
[35,40,42]). Eight studies [35,37e42,44] were performed in mixed
ICUs. Most studies [35,37e39,41e44] included patients on MV at
baseline. In seven studies [35e38,41,43,44] the prevalence of pre-
vious diabetes was 50% whereas three studies [38,39,42] included
no patients with diabetes. The use of corticosteroids was reported
in three studies [36,41,44] and insulin therapy protocols were
described in seven studies [35,36,38,40e42,44]. Severity of illness
was reported in seven studies [36,38,40e44] using APACHE scores
(range, 16.0 to 25.35 points) and in three studies using SOFA scores
[39,41,42].
Eight studies compared a GCF to a standard formulae
[35e37,39,41e44] while two studies [38,40] had two intervention
arms compared to a single control group. The amount of carbohy-
drates in the GCFs (range, 29%e50%) was lower compared to SFs in
all studies. With the exception of one study [43], the amount of
I. Eckert, M.C.C. Kumbier, F.M. Silva et al.
Fig. 1. Flow chart of search and study selection.
protein was fairly similar between treatment groups, ranging from
15% to 23% of total energy prescribed. Detailed information
regarding the dietary composition of the enteral formulae used in
each trial are presented in Table S2 (Supporting Information
Online).
Reporting of glycemic control was highly diverse. All studies
reported data on mean blood glucose but glycemic variability as
assessed in only six studies [37e39,41,43,44], of which four
[38,39,41,44] reported the coefficient of variation; three [37,38,41]
reported the average standard deviation of glucose levels and
three [39,41,43] reported rates of hypo- and hyperglycemic events
with different cut-off points. Other measurements of variability
are further detailed in Table S3 (Supporting Information Online).
The daily amount of insulin administered was reported in eight
studies [36,38e44], of which only two [39,43] had no insulin
protocol described. Mortality was reported in nine studies, either
restricted to ICU events [36,38,44] or as all-location mortality
[35,39e43].
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Clinical Nutrition 40 (2021) 3940e3949
3.2. Assessment of risk of bias and quality of evidence
The risk of bias assessment is summarized in Figs. S1 and S2
(Supporting Information Online). One trial had low risk of bias,
five presented some concerns and four were considered at high risk
of bias. Supporting material for risk of bias assessments are pre-
sented in Table S4 (Supporting Information Online). Summary of
findings in Table 3 shows the GRADE assessment of quality of the
evidence according to each outcome. Overall, quality of the evi-
dence ranged from low to very low.
3.3. Primary outcome: glycemic control
Data from 10 RCTs [35e44] (12 reports) shows that GCFs are
associated with a statistically significant reduction in blood glucose
levels compared to SFs (WMD,
16.06 mg/dL; 95% CI,
23.48
to
8.63 mg/dL; p < 0.001; I2 ¼ 47%) as presented in Fig. 2(A). Visual
inspection of the funnel plot suggests slight asymmetry (Fig. S3,
I. Eckert, M.C.C. Kumbier, F.M. Silva et al. Clinical Nutrition 40 (2021) 3940e3949

Table 2
Characteristics of studies and participants included in the systematic review.

Study features Patient features

Author, year Planned Local Sample Intervention Reported outcomes Attrition Mean Males, BMI, Baseline Prevalence
Duration (Sites, No.) size, formulae rates, No. age, y % kg/m2 glucose of diabetes
No. (%) levels, mg/dL
(SD)

Celaya et al., 1992 14 days Spain (1) 35 Lower in Glucose levels, NR 45.4 65.8 NR >180 mg/dL 2.8%
[35] carbohydrates, mortality
higher in fiber
Mesejo et al., 2003 14 days Spain (2) 50 Lower in Glucose levels, 4/50 (8%) 64.9 81.5 25.2 220.2 ± 69.7 44.2%
[36] carbohydrates, administered
higher in fiber and insulin, MV, ICU
MUFAs LOS, mortality
Egi et al., 2010 [37] 24 h Japan (1) 8 Lower in GV, glucose levels None 64.0 100.0 22.6 130.5 ± 14.5 37.5%
carbohydrates and
glycemic index
Mesejo et al., 2015 28 days Spain (9) 157 Lower in GV, glucose levels, 15/157 58.3 75.8 26.0 150.5 ± 51.0 19.1%
[38] carbohydrates and administered (9.5%)
glycemic index, insulin, MV, ICU
higher in MUFAs LOS, mortality
Wewalka et al., 7 days Austria (1) 60 Lower in GV, glucose levels, 16/60 59.0 46.6 26.9 139 ± 20.4 None
2018 [39] carbohydrates, administered (26.7%)
higher in fiber insulin, mortality
Nourmohammadi 14 days Iran (1) 48 Lower in Glucose levels, None 58.0 70.8 NR 123.4 ± 32.8 None
et al., 2017 [40] carbohydrates administered
insulin, mortality
van Steen et al., 72 h Netherlands 101 Lower in GV, glucose levels, 51/101 66.6 56.4 28.0 147.6 ± 39.6 22.9%
2018 [41] (1) carbohydrates administered (50.5%)
insulin, ICU LOS,
mortality
Vahabzadeh et al., 15 days India (6) 80 Lower in Glucose levels, None 61.5 50.0 NR 224.9 ± 37.7 None
2018 [42] carbohydrates administered
insulin, mortality
Rice et al., 2018 [43] 7 days USA/Canada 105 Lower in GV, administered 8/105 62.1 51.3 33.2 <180 mg/dL 35.3%
(7) carbohydrates; insulin, mortality (7.6%)
higher in protein,
fiber and MUFAs
Doola et al., 2019 48 h Australia (2) 41 Lower in GV, administered 11/41 62.3 58.5 29.1 >180 mg/dL 51.5%
[44] carbohydrates insulin, MV, ICU (27%)
LOS, mortality

Abbreviations: BMI, body mass index; SD, standard deviation; NR, not reported; MUFA, monounsaturated fatty acids; MV, mechanical ventilation; ICU, intensive care unit;
LOS, length of stay; GV, glycemic variability.

Table 3
Summary of Findings: glycemic-control formulae compared to standard formulae for critically ill patients.

3944
I. Eckert, M.C.C. Kumbier, F.M. Silva et al. Clinical Nutrition 40 (2021) 3940e3949

Fig. 2. Forest plot diagrams of the association of glycemic-control formulae (GCF) with (A) blood glucose levels, (B) glucose coefficient of variation and (C) daily administered insulin
as compared to standard formulae (SF).

Supporting Information Online) with non-significant Egger's test
(p ¼ 0.643) for publication bias.
Glycemic variability measured by the coefficient of variation
(CoV) was pooled with data from four studies [38,39,41,44] (5 re-
ports), totaling 359 patients. Figure 2(B) presents a statistically
significant association of GCFs with lower CoV (WMD,
6.85%; 95%
CI,
13.5 to
0.11; p ¼ 0.05; I2 ¼ 95%). Among other measures of GV,
three [37,38,43] out of 4 studies reported a significant reduction of
average SD of blood glucose in the GCF groups (Table S3, Supporting
Information Online).
3.4. Secondary outcomes
The forest plot in Fig. 2(C) presents a statistically significant
association between GCFs and lower daily insulin administered
(WMD,
7.20 IU; 95% CI,
13.92 to
0.48; p ¼ 0.04; I2 ¼ 53%)

3945
I. Eckert, M.C.C. Kumbier, F.M. Silva et al.
Table 4
Subgroup analysis of glycemic-control formulae compared to standard formulae on glucose levels and daily administered insulin.
Subgroup Glucose levels (mg/dL)
Reports, No. WMD (95% CI)
(Patients, No.)
Patients with diabetes
Present 8 (425)
20.60 (
30.04,
11.15)
Absent 4 (265)
4.79 (
17.06, 7.47)
Baseline glucose levels
>180 mg/dL 4 (206)
28.63 (
41.73,
15.52)
<180 mg/dL 8 (484)
9.76 (
15.56,
3.96)
Risk of Bias
With high risk of bias 5 (179)
13.92 (
25.49,
2.36)
Without high risk of bias 7 (511)
17.07 (
27.03,
7.11)
Abbreviations: WMD, weighted mean difference; IU, international units.
compared to SFs, with pooled data from 8 studies (10 reports)
[36,38e44]. Visual inspection of the funnel plot suggests substan-
tial asymmetry (Fig. S4, Supporting Information Online) with a
significant Egger's test (p ¼ 0.029) test.
Pooled data from nine studies [35,36,38e44] (11 reports) shows
no significant association between treatment groups and mortality
(RR, 1.13; 95% CI, 0.82 to 1.56; p ¼ 0.46; I2 ¼ 0%), with no evidence of
publication bias (Fig. S5, Supporting Information Online). The as-
sociation of GCFs was also not statistically significant with duration
of MV (WMD,
0.34 days; 95% CI,
1.72 to 1.04; p ¼ 0.63; I2 ¼ 0%)
across three studies [36,38,44] (four reports) or length of stay in the
ICU (WMD,
0.12 days; 95% CI,
1.77 to 1.52; p ¼ 0.88; I2 ¼ 0%)
across four studies [36,38,41,44] (five reports). Figs. S6eS8 (Sup-
porting Information Online) present the forest plots for secondary
clinical outcomes.
3.5. Subgroup and sensitivity analysis
Subgroup analyses (Table 4) revealed significant associations
with greater magnitude of effect estimates on blood glucose levels
among trials with patients with diabetes and higher baseline
glucose levels. Similar but non-significant associations were found
for insulin requirements in subgroups of diabetes and higher
baseline glucose levels. The association of GCFs with blood glucose
was similar between subgroups according to risk of bias; however,
GCFs were only associated with insulin requirements in studies
without high risk of bias. Sensitivity analyses revealed similar re-
sults for blood glucose levels excluding one crossover trial [37] and
one study [39] that reported plasma blood glucose (Table S5, Sup-
porting Information Online).
3.6. Trial sequential analysis
We have performed trial sequential analyses (TSA) to evaluate the
reliability of our findings regarding blood glucose levels, coefficient
of variation, insulin requirements and mortality (Figs. S9eS12, Sup-
porting Information Online). Findings from TSA suggest that the
available evidence exceeds the required information sizes, with
exception of mortality.
4. Discussion
In this meta-analysis of 10 studies (685 critically ill patients), we
have demonstrated a significant association of GCFs with reduced
blood glucose levels. In subgroup analyses, greater effects on blood
glucose levels were associated with presence of diabetes and higher
baseline levels. The use of GCFs was also significantly associated
Clinical Nutrition 40 (2021) 3940e3949
Administered insulin (IU/day)
I2, % P-value Reports, No. WMD (95% CI) I2, % P-value
(Patients, No.)
63% 0.05 5 (374)
15.84 (
32.03, 0.35) 79% 0.15
0% 5 (265)
2.89 (
9.92, 4.14) 0.0%
47% 0.01 3 (171)
15.26 (
34.83, 4.31) 88% 0.28
0% 7 (468)
3.84 (
10.65, 2.97) 0%
10% 0.69 3 (128)
0.22 (
1.93, 1.49) 0% 0.01
62% 7 (511)
11.55 (
20.49,
2.61) 38%
with lower glucose CoV. Other measurements of variability were
not amenable for statistical pooling due to limited reports of
different metrics. This meta-analysis also shows a significant as-
sociation of GCFs with lower daily insulin requirements. In contrast,
no evidence of significant association was observed for duration of
MV, length of stay in the ICU or mortality. The conclusiveness of
these findings are limited as most studies were judged with at least
some concerns with regards to risk of bias, and confidence in the
evidence ranged from low to very low due to serious imprecision,
unexplained heterogeneity and risk of bias across studies.
Previously conducted systematic reviews [15e18] were limited
to non-critically ill patients, using GCFs as either oral supplements
or tube feeds. These studies have demonstrated similar findings for
short- and long-term improvements in glycemic control. However,
conclusions from the aforementioned meta-analyses were limited
mostly due to imprecision and inconsistency. Our findings are also
in agreement with results of a large RCT [45] that investigated the
effects of a specific strategy of carbohydrate restriction in critically
ill patients. In that trial, a low-carbohydrate enteral formula asso-
ciated with a glucose-free solution of intravenous hydration was
effective at reducing incidence of hypoglycemia and daily insulin
requirements. However, it should be acknowledged that the
glucose target was not consistent between groups, which may
overestimate treatment effects.
Although this study suggests that GCFs are associated with
lower glucose levels, the nature of glycemic control also needs
evaluation in terms of variability [46,47]. Unfortunately, only six
studies in this meta-analysis have reported measures of vari-
ability [37e39,41,43,44]; of those, there were substantial mis-
matches in methods of measurement. Indeed, the existence of
several measures of the same underlying concept of glycemic
variability have been a previously emphasized issue, with the
absence of a gold-standard among dozens of metrics proposed
[48]. The most common measurements among the included RCTs
(average SD of blood glucose and CoV) are also the most
frequently reported metrics in the literature as predictors of
mortality and risk of hypoglycemia [46,48,49]; thus, while it
seems reasonable to include such measures as outcomes in
future trials, we encourage that future investigations adhere to
standardized variability indicators following previously estab-
lished recommendations [50].
Subgroup analyses revealed 3- to 4-fold greater beneficial ef-
fects of GCFs on blood glucose levels and insulin requirements in
studies with patients with diabetes and patients with higher
baseline glucose levels. Similarly, findings from the CoV meta-
analysis show greater effects of GCFs in reports of patients with
unstable glycemic control [38] (defined as CoV  36% [51]). The
3946
I. Eckert, M.C.C. Kumbier, F.M. Silva et al.
limited number of studies and participants warrant caution in
interpreting these exploratory observations [52] for two main
reasons: 1) lack of statistical power within each subgroup may
have led to statistically insignificant findings; and 2) there are
many study-level differences between each subgroup other than
the parameters used for dichotomisation (e.g., studies that
included patients with diabetes may be different in other
measured and unmeasured ways compared to their counterparts),
which could be partially or totally responsible for the observed
differences in effect estimates. Interestingly though, these findings
are in line with the concept of heterogeneity of treatment effects
in critical care settings due to clinical and biological heterogeneity
[53,54] that may affect responsivity to interventions [55,56]. Due
to low credibility, results from subgroup analyses are interpreted
as hypothesis-generating and should be addressed in more
confirmatory studies such as subgroups of larger trials, adequately
powered trials of specific patient populations or individual-patient
meta-analyses with proper meta-regression techniques [57,58].
Further research should also assess outcomes that are sensitive
enough to nutrition interventions and more proximally related to
the physiological effects of GV other than mortality [59], such as
incidence of infections and organ failure [10,60,61].
4.1. Mechanisms of action
In critical illness, the glycemic response to enteral carbohydrate
is greater and sustained for longer, which may further exacerbate
the severity of acute hyperglycemia, leading to increased insulin
requirements and greater risk of blood glucose variability and hy-
poglycemia, which are associated with poor outcomes. A reduction
in glycaemic load by using a diabetes specific formula is associated
with a reduction in the requirement for exogenous insulin and an
improvement in glycaemic variability. Furthermore, low carbohy-
drate formulae were also historically used to assist with manage-
ment of hypercapnea [44]. It therefore seems that the composition
of these formulas, both in quantitative (smaller amount of carbo-
hydrates and higher fat amount) and qualitative aspects (including
modified carbohydrates and MUFA, EPA and DHA), helps reduce
insulin requirements which is a plausible mechanism for reduced
risk of hypoglycemia. For instance, in Mesejo et al. (2015), both GCF
groups had lower frequency of moderate hypoglycemia compared
to a standard formulae group (1.25% and 1.48% versus 3.63%,
respectively; p < 0.05) [38]. Additionally, increasing the fat content
by decreasing the amount of carbohydrate intake can improve
blood glucose control partly because of slowing the gastrointestinal
tract and the slowly absorbing sugars in the diet [42]. It is also
worth noting that changes in proportions of total protein content
provided through enteral formulae is also possibly related to dif-
ferences in glucose excursions, as dietary proteins are associated
with slower gastric emptying; thus, formulations higher in protein
are also likely to exert similar benefits to high-fat formulations as
far as potential mechanisms of action are concerned. The choice of
either enteral formulae higher in carbohydrates or in fat content
should also be made in the context of similar protein content be-
tween comparisons.
4.2. Strengths and limitations
The current study was the first meta-analysis to investigate the
association of specialized enteral nutrition formulae with glycemic
control in critically ill patients, providing a comprehensive over-
view of the available evidence from RCTs. This review was strictly
based on Cochrane recommendations, while following PRISMA
guidelines for appropriate reporting after a prespecified protocol.
We have conducted rigorous methods to judge within-study risk of
3947
Clinical Nutrition 40 (2021) 3940e3949
bias; to assess the certainty in the evidence; and performed plau-
sible subgroup analyses to address heterogeneity and identify po-
tential effect interactions. Trial sequential analyses were also
performed to assess whether results are statistically conclusive
with respect to an optimal information size, suggesting that the
current evidence allows for reliable statistical inferences for its
primary outcome but is insufficient to provide conclusive evidence
for mortality and other clinical outcomes.
There are several limitations to our study and to the available
evidence that should be highlighted. Overall, the body of evidence
herein summarized consists of few trials with relatively small
samples (range, 8 to 157), which may lead to biased estimates due
to small-study effects [62]. Neither visual inspection of the funnel
plot or significance tests were convincingly compatible with risk of
publication bias for blood glucose levels; however, the substantial
asymmetry identified for insulin requirements could reflect not
only publication bias but also selective outcome reporting, inflated
effects due to poor methodological quality or even chance [63].
Many clinical and methodological characteristics reflect on notable
between-study diversity, such as varying levels of attrition rates,
duration of follow-up, duration of interventions, severity of illness
of the included patients, energy intake and within-study preva-
lence of diabetes. Importantly, the amount of energy intake is an
essential nutrition-related variable to be accounted for in proper
analysis of the independent effects of macronutrients. As increased
caloric delivery is associated with exacerbation of insulin re-
quirements and glucose excursions for a given fixed amount of
carbohydrate intake, it is possible that shifting the enteral feeding
to a lower carbohydrate-to-fat ratio has more pronounced effects in
the context of higher rather than lower amounts of energy intake
(i.e., feeding regimens aiming at meeting energy requirements as
compared to trophic or permissive hypocaloric feedings). While we
acknowledge the possibility that the aforementioned study-level
covariates were associated with the observed distribution of ef-
fect sizes, major constraints due to incomplete and heterogeneous
reporting of the primary studies have precluded our statistical
analysis to formally assess the impact of such differences. Addi-
tionally, we were unable to extract outcome data from five studies
[35,37,39,43,44], despite multiple but fruitless attempts to contact
authors for data requests. Notably, meta-analyzable data of CoV and
glucose SD were measured but not reported in two [37,43] and
three studies [39,43,44], respectively.
With regards to the GRADE assessment, we had multiple reasons
for rating down the quality of evidence. First, only one out of 10
studies were judged as at low risk of bias; second, the small sample
sizes and patient-level variability in clinical characteristics across
studies were likely responsible for the imprecision in terms of con-
fidence intervals; and third, meta-analyses were left with a sub-
stantial degree of unexplained heterogeneity even after subgroup
analyses. Based on the GRADE approach to assess the body of evi-
dence, further research is likely to change the effect estimates for
most outcomes due to imprecision, inconsistency and risk of bias.
4.3. Implications for clinical practice
Previous recommendations stated in the most recent ASPEN [11]
and ESPEN [20] guidelines regarding the use of specialized enteral
nutrition for critically ill patients on glycemic control were pre-
dominantly based on a lack of convincing evidence of benefit, with
no systematic attempts to comprehensively review the underlying
body of evidence on glycemic-control (or diabetes-specific)
formulae. The current analyses suggest that GCFs may play a
more important role for glycemic-control than previously thought;
in addition, exploratory subgroup analyses also suggest greater
benefit to those with uncontrolled hyperglycemia (>180 mg/dL)
I. Eckert, M.C.C. Kumbier, F.M. Silva et al.
and diagnosis of diabetes. However, whether specific patient pop-
ulations are likely to benefit from such formulae is a hypothesis yet
to be confirmed. In perspective, this study provides a summary to
inform clinical decisions regarding specialized enteral nutrition in
critically ill patients, which should ultimately be weighted in terms
of potential costs and benefits [64]. Inasmuch as the quality of
evidence is concerned, our findings suggest the use of GCFs as a
promising strategy but several limitations may preclude its trans-
lation to clinical practice, requiring further investigations before
formal recommendations. Our findings extend current knowledge
but should be interpreted with caution due to limited quality of
evidence; thus, we believe larger and better-designed RCTs aimed
to address the evidence gaps highlighted in this review will
contribute to more definitive answers.
5. Conclusions
In this meta-analysis, GCFs were significantly associated with
improved glycemic control and lower insulin requirements among
adult critically ill patients. Although no significant association was
found for clinical outcomes, there is insufficent evidence to confirm
or exclude an important difference for most outcomes due to
serious imprecision in the effect estimates and limited confidence
in results due to overall low quality of evidence. Further research
are needed to address the effects of GCFs in adequately powered
randomized trials.
Funding and sponsorship
Magali Cristini Casola Kumbier received a government-
sponsored scholarship from Coordenaça ~o de Aperfeiçoamento de

via Moraes Silva receives a
Pessoal de Nível Superior (CAPES). Fla
government-sponsored researcher grant for Productivity (Level 2)

gico
from Conselho Nacional de Desenvolvimento Científico e Tecnolo
(CNPq).
Role of the funder/support
CAPES and CNPq had no role in the design and conduct of the
study; collection, management, analysis, and interpretation of the
data; preparation, review, or approval of the manuscript; or deci-
sion to submit the manuscript for publication.
Author contributions
Igor Eckert and Magali C. C. Kumbier have contributed equally
to this work as co-first authors. Igor Eckert and Fla
via Moraes Silva
had full access to all the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis.
Concept and design: Magali C. C. Kumbier, Jussara C. de Almeida,
Igor Eckert; Acquisition of data: Igor Eckert, Magali C. C. Kumbier;
Analysis and interpretation of data: Igor Eckert, Fl

avia Moraes Silva,
Jussara C. de Almeida; Drafting of the manuscript: Igor Eckert,
Magali C. C. Kumbier; Critical revision of the manuscript for
important intellectual content: Igor Eckert, Magali C. C. Kumbier,

via Moraes Silva, Jussara C. de Almeida; Statistical analyses: Igor
Fla

via Moraes Silva; Administrative, technical and material
Eckert, Fla
support: Magali C. C. Kumbier, Jussara C. de Almeida; Supervision:
Jussara C. de Almeida.
Conflict of interest
The authors report no intellectual or financial conflicts of in-
terest related to the material in the manuscript.
3948
Clinical Nutrition 40 (2021) 3940e3949
Acknowledgments
This work is dedicated to the memory of our dear friend,
colleague, and mentor, Jorge Luis Gross, who died in May 2017.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.clnu.2021.04.030.
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