Table 1.

Characteristics of the included studies

Study	Country	Study design	Total sample	Sample		Age (yr)		Male		Control group treatment	Intervention and dosage/route	Outcome in the intervention group
				Intervention group	Control group	Intervention group	Control group	Intervention group	Control group
Sadaka (2019) [38]	USA	Retrospective	62	31	31	67±16	70±12	16 (52)	16 (52)	Managed according to current sepsis guidelines	Ascorbic acid 1.5 g IV every 6 hours for 4 days; hydrocortisone 50 mg IV every 6 hours for 7 days; thiamine 200 mg IV every 12 hours for 4 days IV	ICU mortality, 3 (9.6)
												Hospital mortality, 9 (29)
												Hospital LOS, 15 days (10–22)
												RRT for AKI, 8 (26)
												Duration of VP, 4.5 days (4–6)
												MV-free day, 10.2 (5–15)
Marik (2016) [39]	USA	Retrospective	94	27	47	58.3±14.1	62.2±14.3	27 (100)	23 (49)	Broad spectrum antibiotics, fluids, vasopressors, enteral nutrition, thrombosis prophylaxis, allow permissive hyperglycemia	Ascorbic acid 1.5 g IV every 6 hours for 4 days or until ICU discharge; hydrocortisone 50 mg IV every 6 hours for 7 days or until ICU discharge; thiamine 200 mg IV every 12 hours for 4 days or until ICU discharge	Hospital mortality, 4 (8.5)
												ICU LOS, 4 days (3–5)
												Duration of VP, 18.3±9.8 hours
												RRT for AKI, 3/31 (10)
												Procalcitonin clearance (72 hours), 86.4% (80.1%–90.8%)
Mitchell (2019) [40]	USA	Retrospective	76	38	38	68±10	68±10	36 (95)	37 (97)	IV hydrocortisone alone	Ascorbic acid 1.5 g IV every 6 hours for 4 days; hydrocortisone 50 mg IV every 6 hours or 100 mg IV every 8 hours or continuous IV infusion of 10 mg per hour for 7 days then tapered over approximately 3–5 days; thiamine 200 mg IV every 12 hours for 4 days	Hospital mortality, 18 (47)
												ICU mortality, 12 (32)
												28-Day mortality, 22 (58)
												60-Day mortality, 22 (58)
Litwak (2019) [41]	USA	Retrospective	94	47	47	58.3±17	60.1±14	28 (59.6)	29 (61.7)	Fluid resuscitation with 30 mL/kg of crystalloid, broad spectrum antibiotics, vasopressor therapy	At least one dosage of each of the following medications; ascorbic acid 1.5 g IV every 6 hours; hydrocortisone 50 mg IV every 6 hours or 100 mg IV every 8 hours; thiamine 200 mg IV every 12 hours	Hospital mortality, 19 (40.4)
												ICU mortality, 17 (36.2)
												RRT for AKI, 11/38 (28.9)
												ICU LOS, 11.0 days (7.0–19.0)
												Hospital LOS, 19.0 days (9.0–26.)
												Duration of VP, 84.2 hours (37.0–169.3)
												Delta procalcitonin (72 hours), 0.1 ng/mL (–55.0 to 9.1)
Fujii (2020) [42]	Australia, New Zealand and Brazil	RCT	211a	107	104	61.9±15.9	61.6±13.9	68 (63.6)	65 (62.5)	IV hydrocortisone 50 mg every 6 hours and thiamine 200 mg every 12 hours	Ascorbic acid 1.5 g IV every 6 hours; hydrocortisone 50 mg IV every 6 hours; thiamine 200 mg every 12 hours	28-Day mortality, 24/106 (22.6)
												90-Day mortality, 30/105 (28.6)
												ICU mortality, 21 (19.6)
												Hospital mortality, 25 (23.4)
												28-Day cumulative vasopressorfree days, 25.6 (17.8–26.8)
												28-Day cumulative mechanical ventilation-free days, 25.3 (5.2–28.0)
												28-Day RRT–free days, 28.0 (23.5–28.0)
												28-Day ICU-free days, 21.9 (0–25.8)
												Hospital LOS, 12.3 days (6.2–26.0)
Karimpour (2019) [43]	Iran	RCT	100	50	50	56.2±13.6	61.1±16.9	23 (46)	20 (40)	Normal saline, norepinephrine, hydrocortisone	Ascorbic acid 50 mg/kg IV every 6 hours up to 6 g/day for 4 days; all included patients received hydrocortisone 200 mg daily for 4 days then tapers over 4 days; thiamine 200 mg IV	Delta SOFA score, 9.01±3.92
												28-Day mortality, 8 (15)
												Duration of vasopressors, 77.52±21.5 hours
												ICU LOS, 9.87±8.32
												Mechanical ventilation, 6.67±7.84 days
												Procalcitonin level, 1.25±1.61 ng/mL
Wani (2020) [44]	India	RCT	100	50	50	51.5±35.6	50.7±35.5	31 (62)	28 (56)	Broad spectrum antibiotics, intravenous fluids, vasopressors, and mechanical ventilation as indicated	Ascorbic acid 1.5 g IV every 6 hours for 4 days or until hospital discharge; hydrocortisone 50 mg IV every 6 hours for 7 days or until ICU discharge then tapered over 3 days; thiamine 200 mg IV every 12 hours for 4 days or until hospital discharge	Hospital mortality, 24%
												Duration of vasopressor use, 75.72±30.29
												Hospital LOS, 11.82±7.36 days
												30-Day mortality, 20 (40)
Kim (2018) [45]	Korea	Retrospective	99	53	46	73 (62–79)	74 (68–79)	41 (77)	29 (63)	Managed according to therapeutic recommendations in Surviving Sepsis Campaign Guidelines and lungprotective ventilation strategy	Ascorbic acid 6 g IV divided into 4 equal doses; hydrocortisone 50 mg IV every 6 hours for 7 days then tapered over 3 days; thiamine 200 mg IV every 12 hours for 4 days	Hospital mortality, 6 (17)
												ICU LOS, 9 days (5–14)
												No. ventilator-free days at day 28, 12.3±11.0
												No. vasopressor-free days at day 28, 19.8±10.8
Iglesias (2020) [46]	USA	RCT	137	68	69	70±12	67±14	32 (47)	27 (39)	Saline placebo	Ascorbic acid 1.5 g every 6 hours; hydrocortisone 50 mg every 6 hours; thiamine 200 mg every 12 hours	Delta SOFA score at 72 hours, 2.9±3.3
												Duration of vasopressors, 27±22 hours
												Hospital mortality, 11 (16)
												ICU mortality, 6 (9)
												Hospital LOS, 11.5±6.8 days
												ICU LOS, 4.76±4.3 days
												Procalcitonin clearance, 63 (170)
												Ventilator-free days, 22 (6.2)
												AKI, 54 (79)
Moskowitz (2020) [47]	USA	RCT	200	101	99	68.9±15	67.6±13.9	57 (56.4)	54 (54.6)	Local sepsis guidelines including antibiotics, volume resuscitation and vasopressors	Ascorbic acid 1.5 g every 6 hours for 4 days or until ICU discharge; hydrocortisone 50 mg every 6 hours for 4 days or until ICU discharge; thiamine 100 mg every 6 hours for 4 days or until ICU discharge	All-cause mortality over 30 days, 35 (34.7)
												Kidney failure, 32 (31.7)
												Ventilator-free days, 6 (2–7)
												Shock-free days, 5 (3–5)
												Incidence of delirium, 31/83 (37.4)
												ICU-free days, 22 (3–25)
												All-cause mortality to ICU discharge, 23 (22.7)
												All-cause mortality to hospital discharge, 28 (277)
												Survivors discharged home, 34/73 (46.6)
Vail (2020) [48]	USA	Retrospective	65,299	1,548	63,751	64.6±14.8	66.1±14.7	1,903 (53.2)	168,833 (51.3)	Not mentioned	At least one charge for high-dose IV ascorbic acid along with at least one charge for both IV hydrocortisone and IV thiamine at any dose	Mortality for hospital, 437 (28.2)
Mohamed (2020) [49]	India	RCT	85	45	43	58.7±14.9	59.4±15	31 (69)	32 (74)	Standard of care for septic shock with hydrocortisone and vitamin supplements according to the treating physician’s discretion	Ascorbic acid 1.5 g IV every 6 hours for 4 days; hydrocortisone 50 mg IV every 6 hours for 4 days; thiamine 200 mg IV every 12 hours for 4 days	Mortality, 23/43 (53)
												Time to shock reversal, 34.58±22.63 hours
												Hospital LOS, 20.9±15.01 days
Long (2020) [50]	USA	Retrospective	206	79	127	64.4±13.9	61.1±16.2	43 (54.4)	70 (55.9)	2012 Sepsis Guidelines including 30 mL/kg of crystalloid, broad spectrum antibiotics, and vasopressor therapy; steroids at the discretion of the physician	Ascorbic acid 1.5 g IV every 6 hours; hydrocortisone 50 mg IV every 6 hours; thiamine 200 mg IV every 12 hours	Hospital mortality, 21 (26.6)
												ICU mortality, 9 (11.4)
												Vasopressor duration (median), 13.9 hours
												RRT initiation, 11/74 (14.9)
												Ventilator duration, 3.4 days
												ICU LOS (median), 2.0 days
												Hospital LOS (median), 9.5 days
Chang (2020) [51]	China	RCT	80	40	40	59.5±15	63.7±12.8	22 (57.5)	21 (52.5)	2016 International management of sepsis guidelines including resuscitation, antimicrobial therapy, vasopressor strategy, mechanical ventilation, and RRT	Ascorbic acid 1.5 g IV every 6 hours for 4 days or until ICU discharge; hydrocortisone 50 mg every 6 hours for 7 days or until ICU discharge; thiamine 200 mg IV every 12 hours for 4 days or until ICU discharge	28-Day mortality, 11 (27.5)
												ICU LOS, 7.5 days (4–12.8)
												Duration of vasopressors, 46 hours (23.8–102.5)
												New AKI, 1 (2.5)
												Delta SOFA score (72 hours), 3.5±3.3
												Procalcitonin clearance (72 hours), 75.8 (62.2–86.4)
												Duration of mechanical ventilation, 126.5 hours (63.5–239.3)
												Lactate clearance (72 hours), 21.3% (–49.7% to 44.2%)
Sevransky (2021) [52]	USA	RCT	501	252	249	60.6±13.4	61±16.4	139 (55.2)	134 (53.8)	Matching placebo	Ascorbic acid 1.5 g, thiamine 100 mg, hydrocortisone 50 mg every 6 hours; patients can be given corticosteroids.	Ventilator- and vasopressor-free days, 25 (0–29)
												Mortality at 30 days, 56 (22.2)
												ICU mortality, 52 (20.6)
												Mortality at 180 days, 102 (40.5)
												Length of ICU stay, 6.7 (7.3)
												Length of hospital stay, 12.6 (10)

Values are presented as mean±standard deviation, number (%), or median (interquartile range) unless otherwise indicated.

IV: intravenous; ICU: intensive care unit; LOS: length of stay; RRT: renal replacement therapy; AKI: acute kidney injury; VP: vasopressors; MV: mechanical ventilation; RCT: randomized controlled trial; SOFA: Sequential Organ Failure Assessment.

^aFive patients (2.3%; 2 in the intervention group and 3 in the control group) either withdrew or refused consent to continue participation and withdrew all data, leaving 211 patients.