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) |