Omega-3 fatty acids in the treatment of acute lung injury: a systematic review and meta-analysis

Several randomized controlled trials (RCTs) have compared the treatment of acute lung injury (ALI) with or without omega-3 fatty acids, yet the results remained inconsistent. Therefore, we attempted this meta-analysis to analyze the role of T Omega-3 fatty acids in the treatment of ALI patients.

Omega-3 fatty acids in the treatment of acute lung injury: a systematic review and meta-analysis

Introduction
Acute lung injury (ALI) is a very common type of critically ill disease in the clinic, which is caused by various intrapulmonary and external factors such as severe trauma, shock, acidosis or serious infection et al [1,2]. if left untreated, it may progress into acute respiratory distress syndrome (ARDS) with high mortality [3]. In the past decade, great progress has been made in the management of patients with ALI and ARDS. However, the mortality of ALI/ARDS is still high with a range of 40-31% [4,5]. In addition to infection control, low tidal volume protective lung mechanical ventilation, nutritional treatment of ARDS/ALI plays an important role in the treatment strategies [6][7][8], especially the provision of calories by fat nutrition is a key part [9].
At present, the fat emulsions used in clinical practice are mostly based on soybean oil.
Soybean oil-based fat emulsions are rich in long-chain fat emulsions, which can affect granulocyte activity under severe stress such as trauma and infection, resulting in impaired immune function and increased lipid peroxidation, which in turn increases organ function damage [10,11]. This tendency to increase the inflammatory response often makes the use of soybean oil-based fat emulsions in a dilemma clinically. In recent years, Omega-3 fatty acids have attracted much attention due to their ability to reduce inflammation and regulate immunity. It's been reported [12,13] that it produces the effect of inhibiting inflammation and regulating immunity in many diseases. It has achieved good effects in the treatment of severe patients such as sepsis, systemic inflammatory response syndrome et al [14,15]. Compared to traditional fat emulsions, Omega-3 fatty acids show its superiority in nutritional therapy for critically ill patients [16]. However, the studies on the effects of Omega-3 fatty acids for the treatment of ALI are still lacking.
Based on literature review, we have found that there are several randomized controlled trials (RCTs) focusing on the omega-3 fatty acids in the treatment of ALI, yet the results have remained inconsistent. Furthermore, there aren't related meta-analysis on the role of omega-3 fatty acids in the treatment of ALI, further investigations are needed. Therefore, we have attempted to conduct this meta-analysis to evaluate the efficacy and safety of omega-3 fatty acids in the treatment of ALI, to provide insights into the clinical management of ALI.

Methods
We attempted to conduct and reported this meta-analysis in comply with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [17] Literature search terms were used: "omega-3; fish oil; ω-3 acute lung injury; ALI; acute respiratory distress syndrome; ARDS". We adopted those search terms with combined Boolean operators "AND" or "OR" in every database. Besides, relevant systematic reviews and meta-analyses from these databases were identified, and their bibliographies were scrutinized for further relevant trials, as were those of the RCTs included in the review.

Eligibility criteria
Two investigators independently reviewed the identified articles. The inclusion criteria for RCTs were as follows: (1) RCT design; (2) comparative analysis of ALI treatment with or without omega-3 fatty acids; (3) the details of omega-3 fatty acids treatment and related outcomes were reported. The exclusion criteria were as follows: (1) case reports, reviews, editorial comments, meeting abstracts and articles without applicable data; (2) studies with insufficient data, such as missing the standard deviation (SD);(3) Considerable overlaps between the authors, research centers among the published literature.

Study selection
The search results were imported into the software of Endnote X7 for literature management. Two authors independently reviewed the title, abstract or descriptors of the identified studies and excluded studies that clearly did not meet the inclusion criteria.
After excluding duplicate and apparently irrelevant studies, the full text of the remaining studies was reviewed to assess eligibility for inclusion. Any disagreements were resolved by discussion or by asking an independent third opinion.

Data collection
Two authors independently extracted the data from each study with a standardized data extraction checklist, which included the study characteristics (e.g., first author's name, publication year, journal, country where the study was conducted), characteristics of included study subjects (e.g., number of participants, age, gender distribution et al), details of omega-3 fatty acids treatment intervention, outcome variables (e.g., follow-up period ) and study conclusion. Outcomes were extracted preferentially by intention to treat (ITT) at the end of follow-up. Quantitative data were extracted to calculate effect sizes. Data on effect size that could not be obtained directly were recalculated when possible or contacted the original authors for data. Any discrepancy was resolved by further consensus.

Risk of bias assessment
Two authors independently assessed the methodological quality of the included studies for major potential sources of bias using the Cochrane Collaboration's risk of bias tool, which includes the method of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. We evaluated the methodological quality of every included RCT by rating each criterion as low, high or unclear risk of bias. Any disagreements were resolved through further discussion whenever necessary.

Statistical analysis
Review Manager Version 5.3 software were used for data-analysis. All the data syntheses and interpretations were also performed by two authors independently to ensure the accuracy of the results. Binary outcomes were presented as Mantel-Haenszel-style odds ratios (OR) with 95% confidence intervals (CIs). Continuous outcomes were reported as mean differences (MDs). A fixed-effect model was adopted in cases of homogeneity (Pvalue of χ 2 test > 0.10 and I 2 < 50%), whereas a random-effect model was used in cases of obvious heterogeneity (P-value of χ 2 test > 0.10 and I 2 ≥ 50%). Publication bias was evaluated by using funnel plots, and asymmetry was assessed by conducting Egger regression test. The statistical significance level was 0.05 in this present study.

Results
Study selection

Characteristics of included RCTs
The characteristics of RCTs included in this present meta-analysis are presented in Table   1. Of these included studies, one were performed in India

Outcomes
The changes of PaO 2 Three RCTs [19,20,22] reported the changes of PaO 2 for ALI patients with or without omega-3 fatty acids treatment, the pooled data from the three RCTs revealed that the omega-3 fatty acids treatments significantly improve the PaO 2 in ALI patients (MD =13.82, 95% CI 8.55-19.09, P < 0.001, I 2 = 0%; Figure 4).
The changes of total protein (TP) Three RCTs [18,21,22] reported the changes of TP for ALI patients with or without omega-3 fatty acids treatment, the pooled data from the three RCTs revealed that the omega-3 fatty acids treatments significantly increase the TP in ALI patients (MD =2.02, 95% CI 0.43-3.62, P=0.01, I 2 = 30%; Figure 6).

The duration of mechanical ventilation (MV) Three RCTs[21-23] reported the duration of
MV for ALI patients with or without omega-3 fatty acids treatment, the pooled data from the three RCTs revealed that the omega-3 fatty acids treatments significantly reduced the duration of MV in ALI patients (MD =-1.72, 95% CI -2.84--0.60, P=0.003, I 2 = 0%; Figure   7).
The length of ICU stay Three RCTs[21-23] reported the length of ICU stay for ALI patients with or without omega-3 fatty acids treatment, the pooled data from the three RCTs revealed that the omega-3 fatty acids treatments significantly reduced the length of ICU stay in ALI patients (MD =-1.29, 95% CI -2.14--0.43, P=0.003, I 2 = 59%; Figure 8).

Subgroup and sensitivity analyses
No subgroup analyses were performed in our study because the heterogeneity among included RCTs in the synthesized results remained small. We attempted to evaluate publication bias by using a funnel plot if 10 or more RCTs [24]. However, the number of included RCTs were only six, we could not evaluate publication bias by using a funnel plot.
Sensitivity analyses, which investigate the influence of one study on the overall risk estimate by removing one study in each turn, suggested that the overall risk estimates were not substantially changed by any single study. The pathological feature of ALI is pulmonary edema caused by increased pulmonary capillary permeability, the pathological basis of which is neutrophil-mediated local inflammatory response in the lung [36]. Pathophysiological changes were mainly due to increased Qs/Qt and imbalance of ventilation/blood flow ratio [37]. The application of omega-3 fatty acids not only can quickly reduce the inflammatory reaction of lung tissue, but also transform LTB4, which aggravates inflammatory reaction, into LTB5 series, which is less active, thereby significantly reducing pulmonary edema, improving the pulmonary vascular permeability [38][39][40].

Consent for publication
Not applicable.

Availability of data and materials
All data generated or analyzed during this study are included in this published article.

Competing interests
The authors declare that they have no competing interests.

Funding
None.   Figure 1 The flow chart of study selection Forest plot for the changes of PaO2 Figure 5 Forest plot for the changes of PaO2/FiO2 Figure 6 Forest plot for the changes of TP Figure 7 Forest plot for the duration of MV Figure 8 Forest plot for the length of ICU stay