Methods

This systematic review and meta-analysis was performed according to the PRISMA guideline (Liberati et al., 2009). The study protocol was registered in the PROSPERO international prospective register of systematic review.

Search strategy

PubMed, Scopus, and ISI web of knowledge databases were searched for relevant medical literature without language or publication date restrictions up to September 2019. The keywords used in our search strategy were (“Omega-3 Fatty Acid, γ-Linolenic Acid,Antioxidant Supplementation”). Further details about the search strategy in different databases are provided in Supplementary Table 1. Reference lists of previous reviews that investigated this immunomodulatory formula were also checked for any additional studies not identified by the database searches. All titles and abstracts were screened by two authors (MM and NP) to identify eligible studies.

Eligibility criteria

Titles, abstracts and full texts of retrieved articles were screened by two reviewers (MM and NP) according to the following inclusion criteria:1) the studies were a RCT with either a parallel or crossover design; 2) Study population were adult patients admitted to a ICU; 3) the mean and SDs, SEMs, or interquartile range or 95% CIs for baseline and final values or change values reported for critically ill parameters (length of hospital stays, duration of ICU stays, ICU- free days, duration of mechanical ventilation, ventilator free-days, level of oxygenation, SOFA (sequential organ failure assessment) and MOD (multiple organ dysfunction) score and overall 28 days mortality); 4) the only difference between the treatment group and control was the immunomodulatory formula containing omega-3 fatty acid, γ-linolenic acid and antioxidants. Studies were excluded as per the following criteria: 1) participants younger than 18 years; 2) pregnant and lactating women; 3) trials designed without concurrent controls; and 4) trials that were not performed in ICU settings and subjects were not critically ill.

Data extraction

Data were extracted from the eligible papers by three independent investigators (SF and NP and SR). Data listed from the eligible studies included: first author’s name, country of the study, year of publication, study design underlying diseases, number of participants in the intervention and control group, mean age of the participants and their gender, intervention duration, type of intervention in control and intervention group, before and after measurement of the expected outcomes in the intervention and control group. Outcome included: duration of ICU stays, level of oxygenation (PaO2/FiO2), duration of mechanical ventilation, length of hospital stays, ICU- free days, ventilator- free days, SOFA (sequential organ filure assessment) and MOD (multiple organ disfunction) score, 28 days mortality (for mortality relative risk based on raw data was extracted).

Risk of bias assessment

Two investigators (NP and SR) independently assessed the risk of bias in each included studies on the basis of Cochrane Risk of bias assessment tool (Higgins and Altman, 2008). Disagreements were resolved in consultation with a third investigators (SS). The following criteria were evaluated: random sequence generation, allocation concealment, incomplete data outcome, selective outcome reporting, the blinding of participants and investigators. Each item was classified as yes (low risk of bias), no (high risk of bias) or unclear. The overall quality of included studies was considered as poor if they had less than four points for low risk of bias. They were classified as fair if they had four points and good if they had more than four points for low risk of bias.

Assessment of the quality of meta-evidence

The quality of meta-evidence for this review was evaluated by using the NutriGrade (Grading of Recommendations Assessment, Development, and Evaluation) scoring system (Schwingshackl et al., 2016). This system for systematic review of RCTs has maximum 10 points and includes: 1) risk of bias, study quality, and study limitations, 2) precision, 3) heterogeneity, 4) directness, 5) publication bias, 6) funding bias, 7) study design [22]. The overall quality of meta-evidence for each outcome was classified: high (≥8 points), moderate (6–7.99 points), low (4–5.99), and very low (0–3.99).

Data synthesis and analysis

To determine the clinical effect of immunomodulatory supplements containing γ-Linolenic Acid on potential outcome, changes and standard deviations from baseline within intervention and comparator groups were calculated for each trial. The results were expressed as mean differences (MDs) with 95% CIs. Regarding to malnutrition score (SOFA and MOD), Hedges’g and with 95% CIs were calculated because of different questionnaire applied. For 28-days mortality, relative risk (RR) with 95% CIs were considered as an effect size. Meta-analyses were performed using the inverse-variance weighting method with the random-effects model (DerSimonian and Laird, 1986). Heterogeneity of the included trials was assessed using the chi-squared test and the I2 test (Higgins and Thompson, 2002, Higgins et al., 2011). The substantial heterogeneity was defined as an I2 value of more than 50%. To detect source of heterogeneity a series of predefined subgroup analyses were performed according to 1) underlying diseases (sepsis, ALI and ARDS), 2) quality of the study (good, poor and fair), 3) type of intervention in control group (standard formula and High fat, low carbohydrate formula), 4) duration of intervention (less than 14 days and equal or more than 14 days), 5) mean age of patients (less than 60 years and more than 60 years). The probability of publication bias was checked by funnel plot if the number of included studies for each outcome were at least 10 studies. The sensitivity analysis was performed to evaluate the robustness of finding using a random-effects model (Borenstein et al., 2010). Analyses were conducted using STATA software, version 13 (Stata Corp, College Station, TX). P values less than 0.05 were considered as statistically significant.