Results
Included studies
In total, 166 articles were initially retrieved, and 144 articles were
excluded due to duplication and were irrelevant based on title and
abstract screening. After careful screening of the full texts of the 27
trials, 17 articles were excluded for following reasons: article was
commentary (n=1) (Schott and Huang, 2012), study was the part of another
study (n=1) (Pacht et al., 2003), studies did not have defined outcomes
(n=2) (Nelson et al., 2003, Theilla et al., 2007). Full text was not
available (n=1) (Tang et al., 2008), studies without sufficient data
(n=1) (Elamin et al., 2005), studies conducted in children (n=4)
(Al-Biltagi et al., 2017, Covar et al., 2010, Hamilton and Trobaugh,
2011, Jacobs et al., 2013), articles were not RCT (n=4) (Cohen et al.,
2013, Gadek et al., 1998, Lev and Singer, 2012, Pontes-Arruda, 2005), or
were not conducted on critically ill patients (n=3) (Kalantar-Zadeh et
al., 2005, Remans et al., 2004, Matsuda et al., 2017). In total, 10
clinical trials (1166 participants) were eligible to be included in the
present systematic review and meta-analysis. The Figure 1showed the study screening steps.
Three studies were conducted in USA (Elamin et al., 2012, Rice et al.,
2011, Gadek et al., 1999), two in Israel (Kagan et al., 2015, Singer et
al., 2006), two in Japan (Shirai et al., 2015, Tsukahara et al., 2014),
two in Brazil (Pontes-Arruda et al., 2006, Pontes-Arruda et al., 2011)
and one in Spain (Grau-Carmona et al., 2011). The duration of the
intervention ranged from 7 to 28 days. The mean age of participants
ranged from 42.72-72.5 years. All trials were parallel and conducted in
both gender. Underlying diseases included sepsis, ARDS, ALI, severe
multiple trauma, head and neck cancer with surgery. In all studies,
participants in intervention group received immunomodulatory diet
contains omega-3 fatty acid, γ-linolenic acid and antioxidants. In 4
studies, participants in the control group received high- fat, low-
carbohydrate formula (Elamin et al., 2012, Kagan et al., 2015, Gadek et
al., 1999, Singer et al., 2006) and in 6 studies received standard,
iso-caloric formula (Grau-Carmona et al., 2011, Pontes-Arruda et al.,
2011, Rice et al., 2011, Shirai et al., 2015, Tsukahara et al., 2014,
Pontes-Arruda et al., 2006). The characteristics of the studies included
in the meta-analysis are summarized in Table 1 .
Assessment of risk of
bias
Five studies included in the meta-analysis had a good quality based on
Cochrane Collaboration’s tool (Grau-Carmona et al., 2011, Kagan et al.,
2015, Pontes-Arruda et al., 2011, Rice et al., 2011, Elamin et al.,
2012), four were classified as poor (Pontes-Arruda et al., 2006, Singer
et al., 2006, Gadek et al., 1999, Shirai et al., 2015) and one study was
fair (Tsukahara et al., 2014). In three studies, method of random
sequence generation and method to conceal the allocation of participants
were unclear (Gadek et al., 1999, Pontes-Arruda et al., 2006, Shirai et
al., 2015). In a study by Kagan et al (Kagan et al., 2015) the method to
conceal the allocation of participants was not clear. One study did not
report blinding (Tsukahara et al., 2014), two studies were not double
blind (Shirai et al., 2015, Singer et al., 2006). Blinding of outcome
assessment were not reported for three studies (Pontes-Arruda et al.,
2006, Pontes-Arruda et al., 2011, Tsukahara et al., 2014). Two studies
did not mention incomplete outcome data (Pontes-Arruda et al., 2006,
Gadek et al., 1998) and one had bias in this section (Singer et al.,
2006). No studies reported selective outcome bias (Supplementary
Table 2 ).
Meta-analysis
3.3.1 Level of oxygenation, duration of mechanical
ventilation and ventilator free- days and
Six studies with 709 participants reported the effect of the
immunomodulatory formula on PaO2/FiO2. Meta-analyses comparing this
immunomodulatory formula vs control formula showed no differences
between groups in the effect on PaO2/FiO2 (WMD = 27.40, 95% CI: -7.84,
62.65, P=0.13). The heterogeneity was high (Q statistic=55.44, Cochrane
Q test, P<0.001, I2 =91.0%)(Supplementary Figure 1). In patients with ALI and ARDS,
enhancement in level of oxygenation was statistically significant and
heterogeneity decreased. Both level of oxygenation and heterogeneity
decreased in patients aged <60 years. Heterogeneity in
subgroups of good quality RCTs and in ≥ 14 days intervention decreased(Supplementary Table 3) .
Seven studies with 667 participants reported the effect of the
immunomodulatory formula on duration of mechanical ventilation. This
immunomodulatory formula significantly shortened the duration of
mechanical ventilation in the intervention group compared to control
group (mean difference = -2.20 days, 95% CI: -4.29, -0.10, P=0.04)(Supplementary Figure 2) . The heterogeneity among the included
studies was high (Cochrane Q test=25.86, P<0.001,
I2 =76.8%). In septic and ARDS patients the
immunomodulatory formula significantly reduced duration of mechanical
ventilation compared to other subjects. Also, in patients older than 60
years and in the studies that control group consumed the standard
formula significant reduction of duration of mechanical ventilation was
observed. The reduction of duration of mechanical ventilation in poor
quality RCTs was significant. Underlying disease, age and duration of
intervention were the source of heterogeneity. (Supplementary
Table 4).
Four studies with 629 participants reported the effect of the
immunomodulatory formula on ventilator free- days. There was
non-significant pooled effects of omega-3 fatty acid, γ-linolenic acid
and antioxidant supplementation on ventilator-free days (WMD = 3.37
days, 95% CI: -2.20, 8.85, P=0.24) with high heterogeneity (Q
statistic=31.74, Cochrane Q test, P<0.001,
I2 =90.5%).
3.3.2. Duration of ICU stays and ICU free
days
Eight studies with 901 participants reported the effect of the
immunomodulatory formula on duration of ICU stays. The immunomodulatory
formula shortened the duration of ICU stays by 2.97 days compared to
control group (95% CI: -5.59, -0.35, P=0.02) (Figure 2) ,
between-study heterogeneity was significantly high (Cochrane Q
test=62.55, P<0.001, I2 =88.8%). The
reduction in duration of ICU stays was evident in ALI, ARDS and septic
patients and heterogeneity decreased in these subgroups. Moreover, the
reduced in duration of ICU stays was evident in the studies where
control group received standard formula and in patients more than 60
years old. In the subgroup where the duration of the intervention was
more ≥ 14 days, heterogeneity decreased and the reduction in ICU stays
was statistically significant. Underlying diseases and the quality of
studies were sources of heterogeneity (Supplementary Table 5).
Five studies with 735 participants reported the effect of the
immunomodulatory formula on ICU- free days. This immunomodulatory diet
extended 4.06 ICU- free days in the intervention group than the control
group (95%CI: 0.02, 8.09, P=0.05). The heterogeneity was also high
(Cochrane Q test=39.63, P<0.001, I2 =89.9%)