Days alive and free as an alternative to a mortality outcome in pivotal vasopressor and septic shock trials

RCTs in septic shock negative for mortality may show organ dysfunction benefits. We hypothesized that RCTs in septic shock show significant differences between treatment groups in organ support despite no mortality differences.RCTs of epinephrine vs. norepinephrine plus dobutamine, norepinephrine vs. dopamine and vasopressin vs. norepinephrine reported days alive and free ("DAF") of vasopressors, ventilation and RRT, by subtracting days with support from the lesser of 28 or days to death. We also assigned zero DAF to non-survivors ("DAF and Mortality") and calculated the composite "DAF vasopressors, ventilation and RRT".Using "DAF", norepinephrine was better than dopamine for vasopressors. In contrast, using "DAF and Mortality", norepinephrine was better than dopamine for vasopressors, ventilation and RRT; norepinephrine + dobutamine was better than epinephrine for ventilation. Using the novel composite "DAF vasopressors, ventilation and RRT", norepinephrine + dobutamine was better than epinephrine (p = 0.033), norepinephrine better than dopamine (p = 0.03), and vasopressin better than norepinephrine in less severe shock (p = 0.03).Differences between treatment groups in organ dysfunction in RCTs in septic shock occur despite lack of mortality differences depending on calculation method. If standardized and validated further, DAF could become the primary endpoint of RCTs in septic shock.