Context Several nutrients have been shown to influence immunologic and inflammatory
responses in humans. Whether these effects translate into an improvement in
clinical outcomes in critically ill patients remains unclear.
Objective To examine the relationship between enteral nutrition supplemented with
immune-enhancing nutrients and infectious complications and mortality rates
in critically ill patients.
Data Sources The databases of MEDLINE, EMBASE, Biosis, and CINAHL were searched for
articles published from 1990 to 2000. Additional data sources included the
Cochrane Controlled Trials Register from 1990 to 2000, personal files, abstract
proceedings, and relevant reference lists of articles identified by database
review.
Study Selection A total of 326 titles, abstracts, and articles were reviewed. Primary
studies were included if they were randomized trials of critically ill or
surgical patients that evaluated the effect of enteral nutrition supplemented
with some combination of arginine, glutamine, nucleotides, and omega-3 fatty
acids on infectious complication and mortality rates compared with standard
enteral nutrition, and included clinically important outcomes, such as mortality.
Data Extraction Methodological quality of individual studies was scored and necessary
data were abstracted in duplicate and independently.
Data Synthesis Twenty-two randomized trials with a total of 2419 patients compared
the use of immunonutrition with standard enteral nutrition in surgical and
critically ill patients. With respect to mortality, immunonutrition was associated
with a pooled risk ratio (RR) of 1.10 (95% confidence interval [CI], 0.93-1.31).
Immunonutrition was associated with lower infectious complications (RR, 0.66;
95% CI, 0.54-0.80). Since there was significant heterogeneity across studies,
we examined several a priori subgroup analyses. We found that studies using
commercial formulas with high arginine content were associated with a significant
reduction in infectious complications and a trend toward a lower mortality
rate compared with other immune-enhancing diets. Studies of surgical patients
were associated with a significant reduction in infectious complication rates
compared with studies of critically ill patients. In studies of critically
ill patients, studies with a high-quality score were associated with increased
mortality and a significant reduction in infectious complication rates compared
with studies with a low-quality score.
Conclusion Immunonutrition may decrease infectious complication rates but it is
not associated with an overall mortality advantage. However, the treatment
effect varies depending on the intervention, the patient population, and the
methodological quality of the study.
Nosocomial infection in critically ill patients is associated with higher
morbidity and mortality, prolonged intensive care unit (ICU) and hospital
stay, and increased health care costs.1-3
Among seriously ill patients, malnutrition has been associated with increased
infectious morbidity and prolonged hospital stay.4
Providing nutrition support has become the standard of care for critically
ill patients. Enteral nutrition is preferred to parenteral nutrition for meeting
the nutritional needs of critically ill patients with functioning alimentary
tracts.5
Several specific nutrients such as arginine, glutamine, nucleotides,
and omega-3 fatty acids, either alone or in combination, have been shown in
laboratory and clinical studies to influence nutritional, immunological, and
inflammatory parameters.6-11
To date, there have been several randomized trials that have evaluated the
effect of these immunonutrients on clinically important outcomes. To our knowledge,
2 systematic reviews have already statistically aggregated the results of
these randomized clinical trials in critically ill patients.12,13
However, methodological limitations of the previous reviews weaken the inferences
that can be drawn from them. These reviews included a limited data set since
the authors of each study searched MEDLINE, included articles published in
English,14 and included studies available before
January 1998. One of the meta-analyses12 did
not include some of the key studies on the topic15,16
and included duplicate data.17 The other meta-analysis13 aggregated studies of only 2 commercially produced
formulas without providing justification for not including other formulations.
Given that several studies are available in languages other than English and
that new studies have been published subsequent to the previous reviews, we
undertook a third meta-analysis of immunonutrition.
The purpose of this article is to systematically review, critically
appraise, and synthesize randomized clinical trial data evaluating the effect
of enteral immunonutrients in critically ill patients.
Using text word or MeSH terms randomized, blind, clinical trial, nutrition, arginine, glutamine, omega-3 fatty acids, fish oil, nucleotides, immune, and immunonutrition, we performed
computerized searches for relevant articles on MEDLINE, EMBASE, Biosis, and
CINAHL electronic databases from 1990 to 2000 and the Cochrane Controlled
Trials Register from 1990 to 2000. We contacted the major manufacturers of
"immune-enhanced" formulas and asked for additional published and unpublished
studies. We also searched reference lists of review and original articles,
personal files, and abstract proceedings of recent scientific meetings.
Two of us (D.K.H. and F.N.) screened all citations and classified them
as primary studies, review articles, or other. All primary studies were retrieved
and reviewed independently. We included primary studies if they (1) were randomized
clinical trials; (2) studied critically ill or surgical patients; (3) compared
enteral nutrition supplemented with any combination of arginine, glutamine,
omega-3 fatty acids, or nucleotides compared with standard enteral nutrition;
and (4) included clinically important outcomes, such as mortality, infectious
complications, and length of hospital stay.
To select studies with the greatest validity in terms of relative treatment
effect, we included only randomized clinical trials.18
We excluded the studies reporting only nutritional or immunological outcomes.19 We defined critically ill patients as being routinely
cared for in a critical care environment. Although patients after major surgery
are not necessarily cared for in a critical care environment, we included
studies of elective surgical patients because their response to illness resembles
the hypercatabolic state in critical illness.20
In addition, previous meta-analyses combined data from both surgical and critically
ill patients.12,13
Immune-enhancing nutrients are a group of chemically heterogeneous substances.
Only a small number of clinical trials evaluate the efficacy of a single agent;
most of the studies examine various combinations of these nutrients. We included
studies that compared enteral nutrition containing at least 2 or more of the
4 most frequently used immune-enhancing nutrients (arginine, glutamine, omega-3
fatty acids, or nucleotides) vs standard enteral nutrition only.
Data Extraction and Assessment of Methodological Quality of Primary
Studies
We assessed study method quality by using 9 parameters that influence
the ability of the study to provide a true estimate of treatment effect (Table 1). Using a system5
that we have used in previous analyses, we scored the methodological quality
of individual studies (range, 0-14) and abstracted necessary data in duplicate
and independently. Disagreement was resolved by consensus. We attempted to
contact the authors of included studies and requested further information
not contained in published articles.
Prior Hypotheses Regarding Sources of Heterogeneity
The presence of heterogeneity (or between-study differences in treatment
effect) is a major threat to the validity of meta-analyses. Heterogeneity
weakens, if not invalidates, the overall results obtained from the aggregated
analysis of randomized trials. If present, heterogeneity may be due to differences
across studies in their methods, study populations, interventions, outcomes,
or due to chance. A priori, we postulated that heterogeneity may be explained
by the following hypotheses, which we formally tested in the form of subgroup
analyses.
First, the methodological quality of the primary randomized trials included
in a meta-analysis influences the aggregated results.18
Therefore, we planned to compare studies with higher methodological score
(≥8) to those with a lower score (<8; median score, 8).
Second, there is an increasing number of commercially produced formulations
available on the market. Two of the most frequently studied formulas (Immun-Aid,
McGaw, Irvine, Calif; Impact, Novartis Nutrition, Minneapolis, Minn), which
are similar in arginine content, were compared with the other formulations
(which contain less arginine). We hypothesized that there could be an adverse
effect caused by immunonutrition in critically ill patients with ongoing infection
and sepsis. This may be due to increased production of nitric oxide as a consequence
of arginine supplementation.21
Third, since a previous meta-analysis suggested that the treatment effect
may vary across subgroups of patients,5 we
planned a separate analysis comparing studies of elective surgical patients
with studies of critically ill patients. In the subset of studies of critically
ill patients, we explored whether the treatment effect varied in studies of
differing methodological quality and different products.
The primary outcomes of interest were mortality (ICU and hospital) and
number of patients with new infectious complications. Although no standard
definition was used in all studies, infectious complications included pneumonia,
intra-abdominal abscess, sepsis, line sepsis, wound infection, and urinary
tract infection. The secondary outcomes included length of hospital and ICU
stay and duration of mechanical ventilation. We combined data from all studies
to estimate the common risk ratio (RR) and associated 95% confidence intervals
(CIs) for death and infectious complications. To avoid the problem with bias
and instability associated with RR estimation in sparse data, we added half
to each cell.22 In the meta-analysis, we used
maximum likelihood methods of combining RRs across all trials and examined
the data for evidence of heterogeneity within groups.5,23
The Mantel-Haenszel method was used to test the significance of treatment
effect.24 We used a random-effects model to
estimate the overall relative risk.25,26
Three studies27-29
randomized patients to 3 groups (immune-enhanced enteral formula, standard
formula, and standard total parenternal nutrition). We only included data
from the immune-enhanced enteral and standard enteral groups. For the length
of stay analysis, the effect size (ES) was used to describe the standardized
difference between 2 means from treatment and placebo. Hedges method30 was used for estimating the individual ES and the
pooled effect size between 2 treatments. We considered pooled ES to be more
robust than pooled differences in means because it weights individual studies
according to their sample variance. Since pooled ES is dimensionless, when
we found a statistically significant result using ES, we reported the pooled-simple
differences between 2 group means to provide the estimate of treatment effect
in days. We used the t test for the differences across
subgroups. We considered P<.05 to be statistically
significant.
Study Identification and Selection
We identified a total of 326 citations. Initial eligibility screening
resulted in 60 original articles describing human randomized trials of immunonutrition
selected for further evaluation. Of these, 22 studies met all inclusion criteria
(Table 2).
We reached 100% agreement on the inclusion of articles for this systematic
review. Other randomized studies were excluded because the study evaluated
immune-enhanced formula vs oral diet plus intravenous fluids only,47 2 different formulas both containing immune-enhancing
nutrients,48 formulas containing only one of
the most frequently used immune-enhancing nutrients,49-56
the study results were duplicated in other publications,57-65
or the studies were available in abstract form only.66-68
There were 12 articles and abstracts published by a group of authors
from Milan, Italy.17,27,29,34,57,59,62-64,69-71
We contacted the authors and excluded preliminary reports17,57,59,62,63,69-71
of 3 studies published later.27,29,34
We also excluded 1 article that was in press64
because data from the majority of patients had already been published in another
article27 together with data of other patients.
Effect of Enteral Immunonutrition on Mortality, Infectious Complication
Rates, and Hospital Stay
There were 22 randomized trials involving 2419 patients that compared
the use of immune-enhanced enteral formula with standard formulas. These studies
included evaluations of the experimental enteral formula in patients undergoing
elective surgery,27-29,31-36
critically ill patients with severe trauma,38-43
critically ill patients in an ICU (Ross Products Division of Abbott Laboratories,
unpublished data; 1996),15,16,44-46
and critically ill patients with severe burns.37
The details of each study, including the methodological quality score, are
described in Table 2 and Table 3.
When the results of these trials were aggregated, with respect to mortality,
immunonutrition was associated with no mortality advantage (RR, 1.10; 95%
CI, 0.93-1.31; Figure 1). The test
for heterogeneity was not significant (P = .54),
although a visual inspection of Figure 1
suggests that the treatment effects were variable.
Eighteen studies reported infectious complications in study patients.
The aggregated results of these studies suggest that immunonutrition was associated
with fewer patients with infectious complications compared with standard formulas
(RR, 0.66; 95% CI, 0.54-0.80; Figure 2).
The test for heterogeneity was significant (P<.001).
We aggregated results of 17 studies reporting on length of hospital
stay. Overall, patients receiving immunonutrition had a shorter length of
hospital stay (ES, −0.63; 95 % CI, −0.94 to −0.32; Figure 3). The test for heterogeneity was
significant (P<.001). Using pooled difference
between 2 group means, we also found a shorter length of hospital stay (−3.33
days; 95% CI, −5.63 to −1.02 days).
As there was significant heterogeneity across the studies, we examined
our a priori hypotheses. We compared the trials that used high–arginine-content
formulas (Impact or Immun-Aid) with other formulas of relatively low-arginine
content. There was no difference in mortality for high–arginine-content
studies (RR, 1.05; 95% CI, 0.88-1.25), but we found a higher mortality in
patients receiving immunonutrition in the subgroup of studies using formulas
other than those of high arginine content (RR, 2.13; 95% CI, 1.08-4.21). The P value for the difference between these 2 subgroups was
not statistically significant (P = .06). The rate
of infectious complications was significantly lower in patients receiving
formulas with high arginine content (RR, 0.55; 95% CI, 0.46-0.67) and there
was no difference in the subgroup of formulas other than formulas with high
arginine content (RR, 1.27; 95% CI, 0.74-2.22). The difference in infectious
complications between these subgroups was statistically significant (P = .01). In addition, the subgroup of studies evaluating
formulas with high arginine content was associated with significantly shorter
length of hospital stay (ES, −0.77; 95% CI, −1.09 to −0.45)
in the experimental group; using pooled difference between 2 group means, −4.19
days; 95% CI, −5.52 to −2.86 days. On the contrary, studies of
other formulas showed a trend toward longer hospital stays (ES, 0.37; 95%
CI, −0.09 to 0.83; P = .11). The P value for the difference between these 2 subgroups was .008.
We then compared studies of critically ill patients with studies of
elective surgical patients. In studies of critically ill patients (RR, 1.18;
95% CI, 0.88-1.58) and studies of surgical patients (RR, 0.99; 95% CI, 0.42
2.34), there was no difference in mortality (difference between subgroups, P = .70). In studies of critically ill patients, immunonutrition
had no effect on infectious complications (RR, 0.96; 95% CI, 0.77-1.20). In
studies of elective surgical patients, the number of patients with an infectious
complication was significantly lower (RR, 0.53; 95% CI, 0.42-0.68). The difference
between these subgroups was statistically significant (P = .002). There was a significant decrease in length of hospital stay
in studies of elective surgical patients (ES, −0.76; 95% CI, −1.14
to −0.37); using pooled difference between 2 group means, −3.39
days; 95% CI, −4.55 to −2.23 days. In addition, there was a significant
reduction in length of hospital stay in studies of critically ill patients
(ES, −0.47; 95% CI, −0.93 to −0.01; P = .047); using pooled difference between 2 group means, −3.34
days; 95% CI, −8.27 to 1.45 days. The P value
for the difference between studies of elective surgery and critically ill
patients was .95.
We also compared studies with a methodological quality score of less
than 8 with trials with a score of 8 or more. Trials with a higher methods
score suggested an increase in mortality (RR, 1.19; 95% CI, 0.99-1.43). We
found a trend toward a lower mortality rate in studies with a lower methods
score (RR, 0.74; 95% CI, 0.49-1.14). The difference between these 2 subgroups
was not statistically significant (P = .06). There
were fewer patients with infectious complications in studies with a higher
methodological quality score (RR, 0.53; 95% CI, 0.42-0.68). Studies with lower
quality scores did not show a difference in infectious complications (RR,
1.01; 95% CI, 0.68-1.50). The difference between these subgroups was significant
(P = .01). There was a significant decrease in length
of hospital stay in studies with a higher quality score (ES, −0.67;
95% CI −1.00 to −0.35); using pooled difference between 2 group
means, −3.87 days; 95% CI, −6.63 to −1.12 days. However,
there was no effect on length of hospital stay in studies with a lower quality
score (ES, −0.37; 95% CI, −1.56 to 0.82). The P value for the difference between high-quality and low-quality studies
was .30.
Effect of Enteral Immunonutrition on Critically Ill Patients
Within the subgroup of studies of critically ill patients, we further
examined the effect of immunonutrition on mortality, infectious complications,
and duration of ICU stay and mechanical ventilator use. The overall effect
of immunonutrition in critically ill patients is consistent with no treatment
effect on mortality (RR, 1.18; 95% CI, 0.88-1.58) or rate of infectious complications
(RR, 0.96; 95% CI, 0.77-1.20). However, immunonutrition was associated with
a reduction in length of hospital stay (ES, −0.47; 95% CI, −0.93
to −0.01). In the subgroup analyses, we again found higher mortality
in studies with formulas other than those high in arginine (RR, 2.13; 95%
CI, 1.08-4.21) compared with no effect on mortality in studies with formulas
of high arginine content (RR, 1.03; 95% CI, 0.75-1.41). The between subgroup
difference was not statistically significant (P =
.08). With respect to infectious complications, there was no effect in studies
evaluating formulas other than formulas of high arginine content (RR, 1.28;
95% CI, 0.74-2.22) and there was a trend toward a lower number of infectious
complications in high–arginine-content studies (RR, 0.87; 95% CI, 0.75-1.02).
The P value for the difference between subgroups
was .20. With respect to length of hospital stay, those studies evaluating
formulas of high arginine content were associated with a significantly shorter
length of hospital stay (ES, −0.81; 95% CI, −1.38 to −0.24);
using pooled difference between 2 group means, −7.19 days; 95% CI, −13.25
to −1.08 days. Studies of other formulas showed a trend toward a longer
length of hospital stay (ES, 0.37; 95% CI, −0.09 to 0.83; P = .11); using pooled difference between 2 group means, 6.51 days;
95% CI, −0.06 to 13.10 days. The difference between formulas with high
arginine content and other products was statistically significant (P = .02).
Trials of critically ill patients with higher methodological scores
(≥8) demonstrated a significantly higher mortality associated with use
of immunonutrition (RR, 1.46; 95% CI, 1.01-2.11). There was a trend to decreased
mortality in studies with a lower methodological score (RR, 0.74; 95% CI,
0.49-1.14). The difference between subgroups was statistically significant
(P = .04). There were fewer patients with infectious
complications in trials with a higher methods score (RR, 0.80; 95% CI, 0.64-1.01).
In studies with a lower methods score, immunonutrition was associated with
no effect on complication rates (RR, 1.12; 95% CI, 0.74-1.70). The P value for the difference between subgroups was .20.
With respect to length of hospital stay, those studies with a higher
methodological score were associated with a significantly shorter length of
hospital stay (ES, −0.48; 95% CI, −0.95 to −0.01); using
pooled differences between 2 group means, −5.35 days; 95% CI, −14.90
to 1.21 days. Studies with a lower methodological score showed no difference
in length of hospital stay (ES, 0.27; 95% CI, −2.12 to 1.60). The difference
between these 2 groups was not statistically significant (P = .28).
We also aggregated studies of critically ill patients reporting on number
of days of ventilator use and length of ICU stay. Immunonutrition was associated
with a trend toward a shorter length of ICU stay (ES, −0.36; 95% CI, −0.76
to 0.04) and fewer days of mechanical ventilator use (ES, −0.35; 95%
CI, −0.75 to 0.04). In both cases, the test for heterogeneity was statistically
significant (P<.001).
In this systematic review, we included studies that were recently published,
indexed on databases other than MEDLINE, and published in non-English journals
that were not included in previous meta-analyses.12,13
When the results of the 22 randomized trials were aggregated, we did not find
a statistically significant benefit of immunonutrition on mortality. Immunonutrition
was associated with a statistically significant decrease in the number of
patients with infectious complications and shorter length of hospital stay.
However, the level of heterogeneity of the results across the studies was
significant, precluding us from making strong inferences from the pooled overall
results. Therefore, we performed several a priori–defined subgroup analyses
trying to explain the heterogeneity across the trials. This exercise can be
best viewed as hypothesis-generating rather than hypothesis-confirming.
In contrast to studies evaluating other products, studies evaluating
formulas high in arginine were not associated with an increase in mortality
and were associated with a significant reduction in infectious complications.
Since all studies combined more than 1 specific nutrient, we can only speculate
whether these differences might be due to a different dose of arginine or
other specific nutrients. There is some suggestion from animal studies that
arginine may have a variable response depending on the dose, underlying disease
process, and timing of adminstration.72,73
The effect of immunonutrition in critically ill patients may be systematically
different from the treatment effect in elective surgical patients. Immunonutrition
was associated with significantly fewer infectious complications in elective
surgical patients, but there was no such effect in critically ill patients.
There was a trend toward higher mortality in studies of critically ill patients,
while there was no effect on mortality in elective surgical patients. These
findings are supported by a previous meta-analysis of total parenteral nutrition5 that also demonstrated significant differences in
treatment effect in elective surgical and critically ill patients. Perhaps
these differences are due to differences in underlying pathophysiology, populations
studied, other cointerventions, or outcomes.
Generally, elective surgical patients are at a much lower risk of adverse
outcomes (complications and/or death) than critically ill patients. Following
surgical stress, patients experience some degree of immunosuppression,74,75 increasing their risk for acquired
infectious morbidity and mortality. It follows that immunostimulation in elective
surgical patients may reduce infectious complications. In critically ill patients,
the associated changes to the immune system accompanying critical illness
are complex, variable, and poorly defined. Novel therapies that have been
shown to be effective in critical illness decrease the inflammatory response
rather than stimulate it. We suggest that the results of studies of elective
surgical patients should not be generalized to critically ill patients.
Focusing on the results of the studies of critically ill patients, our
meta-analysis suggests that there is no overall effect of immunonutrition
on mortality, infectious complications, length of ICU stay, or duration of
mechanical ventilation. Immunonutrition is associated with an overall reduction
in length of hospital stay. However, in the subgroup analysis, there is some
evidence that immunonutrition may do more harm than good. Studies using products
other than those high in arginine seem to be associated with an increased
mortality rate and a trend toward increased complications. In addition, studies
of high quality are associated with a significant increase in mortality and
a significant reduction in infectious complications. One possible explanation
for fewer infectious complications and shorter length of hospital stay is
that more patients die and die early in the course of their illness so that
they have a lower chance of becoming infected. This can be supported to some
extent by the largest randomized trial of critically ill patients (contributing
to 45.8% of all deaths in this meta-analysis). In this study, Atkinson et
al15 compared an immune-enhancing formula with
a standard formula in 398 critically ill patients. On an intention-to-treat
basis, 48% of the patients who received the immune-enhancing formula died
compared with 44% in the control group (P = .36).
There was no significant difference in length of hospital or ICU stay. When
the data analysis was restricted to the 25% of the randomized patients who
received a specific amount of enteral nutrition within the first 72 hours,
they found a significant reduction in duration of mechanical ventilation use
and length of ICU stay in patients receiving the immune-enhancing formula.
However, patients receiving immunonutrition also tended to have an increased
mortality rate (P = .16) and to die earlier, which
may explain why length of stay was reduced.
The methodological quality of individual randomized trials has been
shown to influence the overall treatment effect in meta-analyses.5,18 Using a tool that we have used in
previous meta-analyses,5 we evaluated each
individual study for its methodological strengths and weaknesses, weighing
the presence of concealed randomization, double-blinding, and intention-to-treat
analysis more than other criteria. The median score was 8. Post-hoc, we found
that studies that scored 8 or above also had at least 2 of the 3 key criteria
(concealed randomization, double-blinding, and intention-to-treat analysis).
If we accept that the highest-quality studies of critically ill patients offer
the most valid estimate of treatment effect in critically ill patients, this
meta-analysis raises concerns that immunonutrition may do more harm than good
in this population.
Is it plausible that immunonutrition may do more harm than good in critically
ill patients? This hypothesis is consistent with examining individually the
results of 2 large randomized trials of critically ill patients. The first
study, conducted by Bower et al,45 demonstrated
that significantly more patients who received immunonutrition died (RR, 2.00;
95% CI, 1.01-3.75; P = .04). Overall infectious episodes
were similar between both groups. In the subgroup of patients stratified at
baseline as septic, there was a shorter length of hospital stay. However,
mortality in this subgroup receiving immunonutrition was 3 times higher than
that of septic patients who received standard enteral nutrition (11/44 [25%]
vs 4/45 [8.9%]; P = .05). The second study was an
unpublished randomized trial that also demonstrates that immunonutrition is
associated with increased mortality (Ross Products Division of Abbott Laboratories,
unpublished data, 1996). One hundred seventy critically ill patients were
randomized to receive either an experimental diet consisting of supplemental
arginine, omega-3 fatty acids, and vitamins A and E, and β carotene or
isonitrogenous enteral nutrition. There were significantly more deaths in
the group that received the experimental formula (20/87 [23.0%]) compared
with the control group (8/83 [9.6%]; P = .03). However,
there were more patients with pneumonia at baseline in the group that received
the experimental formula compared with patients in the control group. It was
in this subgroup (patients with pneumonia at baseline who received an experimental
diet), in which the excess deaths occurred in the experimental group (10/26
[38.5%]) compared with control group (0/9 [0%]). Therefore, we can only speculate
as to whether stimulating the immune system of infected critically ill patients
may be harmful.
These findings contradict a recently published study by Galban et al.16 This study included 181 critically ill patients who
presented with laboratory or clinical signs of infection on admission to the
ICU and who were randomized to receive Impact or standard enteral nutrition.
The overall results demonstrated that Impact was associated with a significantly
lower ICU mortality (RR, 0.50; 95% CI, 0.25-1.00), but no significant change
in overall ICU acquired infectious morbidity and length of ICU stay. However,
the treatment effect of immunonutrition was only evident in the least sick
group of patients (baseline Acute Physiology and Chronic Health Evaluation
[APACHE] II score, 10-15). There was no mortality advantage among the patients
with the highest baseline APACHE II score who received immunonutrition. This
study was not blinded, did not report on cointerventions, and dropped randomized
patients from the analysis. Among 13 randomized trials of critically ill patients,
there are no other studies, apart from that of Galban et al,16
which demonstrate a clear improvement in mortality associated with immunonutrition.
Our study has several limitations. First, as we excluded studies of
single immune-enhancing agents,49-56
the results of our meta-analysis are not applicable to single interventions.
Second, our method of scoring the quality of each trial did not allow us to
determine which component of quality was most important. Third, we did not
apply meta-regression techniques to determine if there are confounding effects
between different variables explaining the heterogeneity.
In conclusion, immunonutrition may decrease infectious complication
rates. However, the treatment effect varies depending on the patient population,
the intervention, and the methodological quality of the study. In elective
surgical patients, immunonutrition is associated with a reduction in infectious
complication rates and a shorter length of hospital stay without any adverse
effect on mortality. However, in critically ill patients, immunonutrition
is not associated with any apparent clinical benefits and it may be harmful
in some subgroups of patients. Given the methodological weaknesses of the
primary studies, their sample size, and the suggestion that immunonutrition
may be associated with an increased mortality in critically ill patients (as
evidenced by the studies with a higher methods score), we cannot recommend
immunonutrition to all critically ill patients. Further research needs to
define the underlying mechanism by which immunonutrition may be harmful and
to identify which products and which patients are associated with clinical
benefit.
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