Antioxidant micronutrient supplementation in critically ill adults: A systematic review with meta-analysis and trial sequential analysis

Abstract

The role of antioxidant micronutrient (AxM) supplementation in the critically ill patients has been controversial, and recent trials have suggested a tendency to harm. Therefore, we performed a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized controlled trials (RCT) to examine the effect of AxM supplementation on clinical outcomes among critically ill adults. PubMed, EMBASE, Cochrane, CINAHL, LILACS, DARE, SCOPUS, and Web of sciences databases were searched from inception to March 2019. RCTs that compared AxM supplements with placebo in adult critically ill patients and reporting mortality as an outcomes were included. Trial quality was assessed using updated cochrane risk of bias (RoB-II) tool. Primary outcome was all-cause mortality. Secondary outcomes were 28-day mortality, intensive care unit (ICU) and hospital length of stay (LOS), ventilator days and infection between the two groups. Outcomes were summarised using random-effects estimators. Quality of evidence (QOE) was rated using Grading of Recommendations, Assessment, Development and Evaluation. Prior to final analysis, we repeated the search through September 2019. R version 3.6.2 and STATA version 13 were used for all statistical analyses. Pooled analysis of 34 trials with 4678 patients revealed that AxM supplementation was associated with possible reduction in all-cause mortality (relative risk [RR], 0.89 [95%CI 0.79 to 0.99], TSA adjusted CI 0.77 to 1.03; Low QOE). Fragility index and number needed to treat were 1 and 41, respectively. Eight studies with low RoB (RR, 1.08; 95%CI 0.95 to 1.23; TSA CI, 0.64 to 1.82; moderate QOE) did not show mortality reduction with AxM supplementation. ICU LOS (weighted mean difference [WMD],-0.84; 95%CI -1.50 to-0.18; moderate QOE), hospitalization days (WMD,-2.83; 95%CI -3.91to-1.75; low QOE) and ventilator days (WMD,-1.87; 95%CI -3.60 to-0.14; very low QOE) showed a statistically significant benefit with AxM supplementation. In meta-regression analysis, neither the duration of AxM therapy nor the dosage of selenium, which was the most widely studied AxM, reported an association with mortality. Although AxM supplementation was associated with possible reduction in all-cause mortality, results from the TSA and studies with low RoB showing null effect suggest that the evidence of benefit is questionable. Secondary outcomes attained statistically significant benefit with AxM supplements, but the certainity of evidence was low. To summarize, current evidence does not justify administration of AxM in critically ill patients. PROSPERO, CRD42019125898.