We obtained ethics approval for this study (18/LO/1079). VANISH was a 2 × 2 factorial, double-blind, RCT in adult patients with sepsis who required vasopressors, in 18 general adult intensive care units (ICUs) in the United Kingdom (UK) [
13]. In the VANISH trial [
13], patients were randomly allocated to vasopressin and hydrocortisone (
n = 101), vasopressin and placebo (
n = 104), norepinephrine and hydrocortisone (
n = 101) or norepinephrine and placebo (
n = 103). Patients only received the second study drug (hydrocortisone/placebo) if the maximum infusion of the first study drug (vasopressin/norepinephrine) had been reached. Therefore, in the hydrocortisone analysis, only participants who received the study drug were included (hydrocortisone
n = 148, placebo
n = 148); all remaining analyses are intention-to-treat. The 28-day mortality was 63/204 (30.9%) of patients in the vasopressin group and 56/204 (27.5%) patients in the norepinephrine group (difference = 3.4% [95% CI, − 5.4–12.3%]) [
13]. LeoPARDS was a two-arm parallel group, double-blind, placebo-controlled RCT in adult patients with sepsis who required vasopressors, in 34 ICUs in the UK [
13]. In LeoPARDS trial [
14], patients were randomised to receive either levosimendan (
n = 258) or placebo (
n = 257) over 24 h in addition to standard care. The 28-day mortality was 89/258 (34.5%) in the levosimendan group and 79/256 (30.9%) in the placebo group (difference = 3.6% [95% CI, − 4.5–11.7%]) [
14]. HARP-2 was a two-arm parallel group, double-blind, placebo-controlled RCT in adult patients within 48 h after the onset of ARDS in 40 ICUs in the UK and Ireland [
15]. In the HARP-2 trial [
15], patients were randomised to receive either once-daily simvastatin or identical placebo tablets enterally for up to 28 days. The 28-day mortality was 57/259 (22.0%) in the simvastatin group and 75/280 (26.8%) in the placebo group (risk ratio = 0.8 [95% CI, 0.6 to 1.1]) [
15].
]