Discussion
The meta-analyses from ten RCTs revealed that an enteral
immunomodulatory diet (omega-3 fatty acid, γ-linolenic acid and
antioxidant supplementation) significantly shortened duration of
mechanical ventilation and ICU stays, extended ICU-free days, reduced
SOFA and MOD score and overall 28 days mortality in critically ill
patients.
Our finding showed that enteral immunomodulatory containing omega-3
fatty acid, γ-linolenic acid and antioxidant improved the respiratory
functions in ICU patients. Our results are similar to a review of 6
clinical trials (Lev and Singer, 2012) in ALI/ARDS patients concluding
that the use of formula enriched with omega-3 and GLA could improve
oxygenation and clinical outcomes. The n-3/n-6 ratio of fatty acids
could have important role in the alveolar cytokines release (Lev and
Singer, 2012). A mechanisms for a protective effect of omega-3 fatty
acids in the lungs might be resulting from the products of EPA and DHA
which resolves mediators, including resolvins, protectins and maresins
found within the lung and circulation (6). Resolving these mediators
regulates neutrophil infiltration, cytokine production, clearance of
inflammatory leucocytes and inflammatory response, which ultimately
helps to maintain the integrity of the lung membrane (Lemoine et al.,
2019).
Evidence support the relationship between imbalanced oxidant homeostasis
and lung disease showing a trend for potential benefit of antioxidant
supplementation in respiration function (Tashakkor et al., 2011).
Actually, antioxidant supplementation increases antioxidant capacity
like reduced glutathione levels, which subsequently decreases oxidative
stress (Mudway et al., 2004).
The SOAF and MOD score evaluates organ failure in critically ill
patients (Zygun et al., 2006). This study showed that immunomodulatory
diet reduced organ failure. This finding is consistent with the results
of Shirai et al (Shirai et al., 2015) and Elamin et al (Elamin et al.,
2012) where these improvements in patient status lead to decreased
duration of ICU stays and increased ICU-free days. On the other hand,
this study showed significant reduction in duration of mechanical
ventilation and increased PaO2/FiO2 and ventilator free days in ARDS
patients. These results have been well illustrated in Shirai (Shirai et
al., 2015) and Gadek (Gadek et al., 1999) studies.
Another review claimed that the beneficial effect of this
immunomodulatory formula related to its omega-3 fatty acids composition
and adverse outcome in critically ill patients is due to excess
production of proinflammatory cytokines and eicosanoids from other
polyunsaturated fatty acids (Das, 2013). When the balance between
proinflammatory and anti-inflammatory molecules is upset as in critically
ill patients, it would lead to persistence of inflammation and
progressive cell/tissue and organ damage (Das, 2013). In sepsis, ARDS,
ALI and other systemic inflammatory conditions, not only an extend in
proinflammatory molecules such as IL-6, TNFα, but also a decrease in the
production and action of anti-inflammatory molecules such as IL-4, IL-10
occurrs (Das, 2013). Therefore, supplementation with formula containing
omega-3 fatty acid, γ-linolenic acid and antioxidant may help to
maintain the balance between proinflammatory and anti-inflammatory
conditions.
According to previous meta-analysis (Li et al., 2015), the enteral
immunomodulatory diet did not extend ICU- free days, ventilator- free
days and any significant reduction in the risk of all-cause mortality.
The beneficial effect of this formula on reducing risk of mortality
indicated only in patients with high mortality. Our result is
inconsistent with these reports because of addition of 3 more studies
(Pontes-Arruda et al., 2011, Shirai et al., 2015, Kagan et al., 2015)
compared to the previous meta-analysis. Our study considered all the
studies conducted in critically ill patients, while previous
meta-analysis was restricted to only ARDS and ALI patients. However, the
findings from our subgroup analysis contrary to previous meta-analysis
showing a decrease in all cause 28 days mortality in ARDS and ALI
patients. The significant impact of this immunomodulatory diet on
mortality should be interpreted with caution, because not only a small
number of studies have examined the effect of this immunomodulatory
formula on mortality but also this reduction is based on estimated raw
data and we could not adjust the impact of other important confounders
such as age, severity of injury and body weight.
Gastrointestinal dysfunction such as diarrhea, dyspepsia and nausea were
reported as the main adverse effects of this formula (Li et al., 2015).
However, it may result from intolerance response to the rate of
continuous enteral infusions in patients (Li et al., 2015). Rice et al
(Rice et al., 2011) solved this problem by using a bolus delivery,
namely small-volume approach. Also, the components of this supplement
are within the tolerance range and are safe.
To test the robustness of the results, we conducted sensitivity
analyses. We excluded each individual study, re-analyzing and comparing
with the original results. When excluding the trial conducted by Rice et
al (Rice et al., 2011), the overall effect for ICU-free days and
ventilator-free days became significant suggesting that these outcomes
increase in non- ALI patients. When excluding other trials, the results
were consistent with a previous report (Li et al., 2015).
Some limitations in this report should be mentioned. First, the sample
sizes of the included trials were small. Second, there was one study for
some critical diseases like multiple trauma and head and neck cancer.
Therefore, we cannot conclude with certainty about supplementation in
these patients. Third, for mortality there were few studies (n=9 and
sample size=1104) and there was not any clinical trial for long- term
mortality (more than 3 months). Also, we reported the risk ratio of all
cause 28 days mortality and we could not adjust the impact of other
important confounders such as age, severity of injury and body weight.
However, due to the randomness of all the included studies, many
confounding variables were similar between the intervention and control
groups. The effect of this formula requires a longer-term follow up to
show its effect on mortality. Forth, we did not have enough data for
biochemical and hematological markers and these outcomes could be
important to judge about the overall effect of this formula. Finally,
according to NutriGrade the meta- evidence for all outcomes were
moderate and for level of oxygenation (PaO2/FiO2) was low. Therefore
more well-designed studies with larger sample size and long term
follow-up of mortality are recommended.
The strength of this study was the adoption of comprehensive search
strategy without language and time restrictions. We used Nutrigrade tool
to evaluate the quality of each outcome. Compared to previous
meta-analysis (Li et al., 2015), our study included more studies and
variables including length of hospital stays, duration of ICU stays,
duration of mechanical ventilation, level of oxygenation, SOFA and MOD
score. In addition, we performed several subgroup analyses to identify
the source of heterogeneity