Table 1. Review of studies on high-dose ascorbic acid (Vitamin C) in critically ill patients with sepsis.

Study	Design	Patients	Intervention arms	Time to treatment; and hydrocortisone exposure prior to randomization	Main and mortality outcomes
Marik et al., Chest 2017 (28)	Propensity adjusted single institution pre-post study	94 adults with sepsis/ septic shock in ICU	Hydrocortisone (50 mg q6h)/Vitamin C (1.5 g q6h)/thiamine (200 mg q 12h) in n=47 vs. historical group [n=47, of which n=28 (59.6%) received hydrocortisone]	N/A	Mortality 8.5% treatment vs. 40.4% control (adjusted OR 0.13; 0.04 to 0.48; P=0.002)
Wald et al., Am J Respir Crit Care Med 2020 (44)	Single centre propensity-matched observational	557 children with septic shock in ICU	Hydrocortisone (50 mg/m2)/Vitamin C (30 mg/kg q6h)/thiamine (4 mg/kg/d) in n=43 vs. hydrocortisone in n=181 vs. n=333 controls	Median 12 h (IQR 6–19 h) from PICU admission to start of metabolic resuscitation	Mortality 28% control vs. 30% hydrocortisone alone vs. 9% intervention (adjusted OR 0.3; 0.1 to 0.9; P<0.05)
CITRIS-ALI; Fowler et al., JAMA 2019 (61)	Blinded multicentre RCT	167 adults with sepsis and ARDS in ICU	Vitamin C [50 mg/kg q6hrs in n=84, of which n=56 (67%) received hydrocortisone] vs. placebo in n=83 [of which n=54 (65%) received hydrocortisone]	N/A	Mortality 46.3% placebo vs. 29.8% intervention (difference 16.6%; 2% to 31.1%, P=0.03)
VITAMINS; Fuji et al. JAMA 2020 (62,63)	Open label multicentre, international RCT	216 adults with septic shock in ICU	Hydrocortisone (50 mg q6h)/Vitamin C (1.5 g q6h)/thiamine (200 mg q 12h) in n=109 vs. hydrocortisone (50 mg/kg q6h) in n=107	Time from meeting eligibility criteria to the first dose median 12.1 hrs (IQR 5.7–19.0) intervention, and 12.9 hrs (4.0–15.0) for control	Mortality 22.6% intervention vs. 20.4% control (difference 2.3%; −8.9% to 13.4%; P=0.69)
ORANGES; Iglesias et al., Chest 2020 (64)	Single centre double blind, placebo controlled RCT	137 adults with septic shock in ED	Hydrocortisone (50 mg q6h)/Vitamin C (1.5 g q6h)/thiamine (200 mg q12h) in n=68 vs. n=67 controls [of which n=28 (41%) received hydrocortisone]	Time between presentation to ED and first dose of study drug mean 9.9±4.5 hours	Time to shock reversal 27±22 hrs intervention vs. 53±38 hrs controls, (P<0.001); ICU mortality 9% vs. 14% (P=0.37)
ACTS; Moskovitz et al., JAMA 2020 (65,66)	Multicentre double blind, placebo controlled RCT	200 adults with septic shock in ICU	Hydrocortisone (50 mg q6h)/Vitamin C (1.5 g q6h)/thiamine (100 mg q6h) in n=101 vs. placebo in n=99 [of which n=14 (14.1%) received open-label corticosteroids after enrolment]	Time from vasopressor initiation to first study drug median 14.5 hrs (IQR 8.1–19.1) intervention versus 13.0 hrs (7.5–20.5) placebo	Mortality 34.7% intervention vs. 29.3% control (hazard ratio, 1.3; 95% CI: 0.8–2.2; P=0.26)
ATESS; Hwang et al., Intensive Care Med 2020 (67)	Multicentre double blind, placebo controlled RCT	111 adults with septic shock in ED	Vitamin C (50 mg/kg max 3 g q12h)/thiamine (200 mg q12h) in n=53 (of which 58.5% received hydrocortisone) vs. placebo in n=58 (of which 50% received hydrocortisone)	time from ED arrival to first study drug administration median 8.4 h (IQR 5.7–14.9) intervention and 9.9 h (IQR 7.4–15.6) placebo	28-d mortality 20.8% intervention vs. 15.5% control (P=0.47)
Coloretti et al., J Crit Care 2020 (68)	Propensity-matched single centre pre-post study	137 adults with septic shock in ICU	Hydrocortisone (240 mg/d infusion)/Vitamin C (1.5 g q6h)/thiamine (200 mg q12h) in n=56 vs. hydrocortisone in n=56	N/A	Length of mechanical ventilation 3d intervention vs. 6d controls (P=0.012). Hospital mortality 50.0% intervention vs. 60.7% control (P=0.25)
VICTAS; Sevransky et al., JAMA 2021 (69)	Multicentre double blind, placebo controlled RCT	501 adults with septic shock planned to be admitted to ICU	Hydrocortisone (50 mg q6h)/Vitamin C (1.5 g q6h)/thiamine (100mg q6h) in n=252 vs. placebo in n=249	time between onset of qualifying organ dysfunction and first dose of study drug 15 hours median (IQR 8–22 hours); 33% hydrocortisone treatment pre-randomization	Ventilator- and vasopressor-free days 25 days intervention versus 26 days placebo (P=0.85). 30-d mortality 22% intervention vs. 24% control (unadjusted OR 0.900, 95% CI: 0.594–1.363, P=0.619)