Fig. 4

Trial sequential analysis: 24-h mortality (a), 1-month mortality (b). [How to read the figure: In blue is the cumulative Z-curves calculated after including subsequent trial into the meta-analysis. A reference line at two-sided Z = 1.96 (equal to a p = .05) is drawn, and it is usually considered the significant result threshold in meta-analysis. Trial sequential monitoring boundaries are reported in red. To obtain reliable evidence (pros or cons of the intervention), the cumulative Z-score must cross the red line. The futility area is dyed in green. If the cumulative Z-score hit the futility area, the result of the meta-analysis is for no effect (neither negative nor positive) of the intervention. On the far right of the figure is the line with the sample size calculation according to the trial sequence analysis methodology]