Table 2.
Narrative summary of included studies.
| ID | Population | Intervention | Comparisons | Outcome |
|---|---|---|---|---|
| Abdoulhossein et al., 2018 [42] | N = 40 [T = 20, C = 20] Age (mean ± SD): T = 40.35 ± 8.94, C = 39.95 ± 9.05 Gender, n (%); Male: T = 14(70%), C = 12(60%) GCS, n (%) 13: T = 1 (5%) C = 1(5%) 14: T = 6 (30%) C = 5 (25%) 15: T = 13 (65%) C = 14 (70%) | Intravenous infusion vitamin C (500 mg in 50 mL normal saline) was administered by pump, steady, for up to 30 min along with standard of care. | The control group received intravenous infusion distilled water (5 mL in 50 mL of normal saline), by pump, steady, for up to 30 min. | ICU stay after intervention, days T = 5.5 ± 1.73 C = 5.2 ± 1.67 |
| Ahn et al., 2019 [19] | N = 75 T = 35 C = 40 Age, mean ± SD (years) T = 67.8 ± 12.1 C = 63.6 ± 15.3 Sex, male, n [%] T = 24 [43] C = 29 [44] APACHE II score T = 25.2 ± 6.1 C = 24.1 ± 6.0 Day 1 SOFA score T = 10.3 ± 3.3 C = 11.3 ± 3.1 Vasopressors, n [%] T = 33/35 [94] C = 40/40 [100] Hydrocortisone, n [%] T = 16/35 [45] C = 27/40 [46] Creatinine, mean ± SD, mg/dL T = 1.74 ± 1.81 C = 2.15 ± 1.81AKI, n [%] T = 21/35 [47] C = 28/40 [74] |
A total of 2 g of vitamin C mixed in 50 mL of 5% dextrose solution or normal saline was administered intravenously over 30 min every 8 h until ICU discharge. | Treatment protocol based on the Surviving Sepsis Guidelines. Patients could receive hydrocortisone to maintain blood pressure if required. | 28-day mortality, n [%] T = 12/35 [34] C = 8/40 [20] 90-day mortality, n [%] T = 21/35 [48] C = 19/40 [49] ICU mortality, n [%] T = 12/35 [34] C = 12/40 [30] Hospital mortality, n [%] T = 16/35 [45] C = 16/40 [40] Shock reversal, days T = 3 [2,3,4,5] C = 3 [2,3,4,5] Mechanical ventilation, days T = 8 [5,6,7,8,9,10,11,12,13,14,15,16,17] C = 8 [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19] ICU LOS, days T = 10 [6,7,8,9,10,11,12,13,14,15,16,17,18,19] C = 11 [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35] Hospital LOS, days T = 23 [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40] C = 41 [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,45,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66] ΔSOFA score, first 4 ICU days T = −1.4 ± 3.3 C = −1.4 ± 3 RRT for AKI, n [%] T = 14/28 [55] C = 19/31 [65] Recovery from AKI, T = 13/28 [45] C = 16/31 [57] Total AKI, n T = 28/35 C = 31/40 New AKI during treatment: T = 7/35 C = 3/40 |
| Balakrishnan et al., 2018 [50] | N = 24 [T = 12, C = 12] Age, mean: T = 55.41 ± 15.70; C = 53.41 ± 8.27 Male, n (%) T = 8(66.6), C = 7(58.3) Euroscore II T = 1.95 ± 1.29 C = 2.78 ± 4.06 APACHE IV Score T = 60.91 ± 17.52 C = 51.81 ±10.76 | Intravenous vitamin C (1.5 g every 6 h for 4 days), hydrocortisone (50 mg every 6 h for 4 days) as well as intravenous thiamine (200 mg every 12 h for 4 days). The vitamin C was administered as an infusion over 30–60 min and mixed in a 50-milliliter solution of either 5% dextrose in water (D5W) or normal saline. | Received saline in a black syringe. | Urea (mg/dL) Day 1: T = 76.12 ± 47.18; C = 75.29 ± 46.96 Day 2: T = 79.85 ± 59.84; C = 71.03 ± 50.76 Day 3: T = 90.61 ± 66.78; C = 89.64 ± 59.73 Day 4: T = 89.58 ± 56.55; C = 93.43 ± 52.48 Creatinine (mg/dL) Day 1: T = 2.73 ± 2.16; C = 1.52 ± 0.79 Day 2: T = 2.17 ± 1.33; C = 1.43 ± 0.81 Day 3: T = 2.24 ± 1.33; C = 1.59 ± 0.75 Day 4: T = 2.25 ± 1.46; C = 1.68 ± 0.84 |
| Bedreag et al., 2015 [20] | N = 34 [T = 20 C = 14] Gender, % male; T = 75 C = 85.71 Age, mean (SD), years T = 52 (14.5) C = 53.8 (20.9) APACHE II, mean (SD) T = 10.7 (5.8) C = 10.8 (7.6) ISS, mean (SD) T = 26.1 (8,4) C = 31.1 (9.4) GCS < 7, n (%) T = 1 (5) C = 6 (42.8) Urea (mg/dL), T = 59.5 (10.5) C = 64.1 (3.1) |
Antioxidant therapy consisted of the administration of vitamin C, vitamin B1 and N-acetylcysteine (NAC).All patients received vitamin C (i.v): 1 g three times daily, for 5 days; vitamin B1 (i.v.): 100 mg daily for 3 days; and N-Acetylcysteine (i.v.): 300 mg twice a day, for the whole period of the ICU stay. | Standard of care. | Incidence of sepsis T = 8/20 C = 9/14 LOS in ICU T = 11.7 ± 11.9, C = 13.2 ± 13.9 Mortality T = 6/20 (30%) C = 9/14 (64.2%) Urea (mg/dL), mean (SD) at discharge from ICU T:27.8 (10.5); C: 57.1 (20.8) |
| Chang K et al., 2020 [21] | N = 140 T = 52 C = 88 Age, mean (SD) T = 63.9 (15.7) C = 63.6 (14.5) Female, n (%) T = 21 (40) C = 34 (39) APACHE IV, T = 95.1 (32.3) C = 86.1 (28.4) SOFA, T = 9.9 (3.8) C = 8.6 (3.1) Vasopressors, n (%) T = 51 (98) C = 85 (97) |
Vitamin C at a dose of at least 1500 mg every six hours for up to 96 h. | Patients were treated following the Surviving Sepsis Campaign guidelines. | Hospital death, n (%) T = 20/52(39) C = 32/88 (36) ICU death, n (%) T = 16/52 (31) C = 20/88 (23) Ventilator-free days, T = 16.0 (11.8) C = 17.8 (11.8) Vasopressor-free days, T = 16.9 (11.8) C = 19.7 (11.5) ICU LOS, mean (SD) T = 11.1 (13.3) C = 9.3 (11.7) Dialysis, n (%) T = 23/52 (44) C = 39/88 (44) Vasopressors, n (%) T = 51 (98) C = 85 (97) |
| Chang P et al., 2020 [51] | N = 80 T = 40 C = 40 Age, y T = 59.5 ± 15.0 C = 63.7 ± 12.8 Sex, male T = 22 (57.5) C = 21 (52.5) Mechanical ventilation T = 30 (75) C = 32 (80) Vasopressors T = 22 (55) C = 24 (60) SOFA score T = 9.6 ± 4.5 C = 10.1 ± 4.0 APACHE II score T = 22.1 ± 8.4 C = 23.8 ± 7.6 CRF n (%) T = 4/40 (10) C = 5/40 (12.5) AKI n (%) T = 17/40 (42.5) C = 21/40 (52.5) |
IV hydrocortisone (50 mg every 6 h for 7 days or until ICU discharge, whichever occurred first), vitamin C (1.5 g every 6 h for 4 days or until ICU discharge, whichever occurred first), and IV thiamine (200 mg every 12 h for 4 days or until ICU discharge, whichever occurred first) | Same frequency and volume of saline. | 28-d mortality T = 11/40 (27.5) C = 14/40 (35) ICU LOS, d T = 7.5 (4–12.8) C = 7.5 (4–11.8) Duration of vasopressors, h T = 46 (23.8–102.5) C = 58.5 (28–104) New AKI after entering ICU T = 1/40 (2.5) C = 2/40 (5) Change in SOFA score, 72 h T = 3.5 ± 3.3 C = 1.8 ± 3.0 Duration mechanical ventilation, h T = 126.5 (63.5–239.3) C = 94.5 (39.8–211) Lactate clearance, 72 h, % T = 21.3 (−49.7 to 44.2) C = 0 (−35.1 to 47.7) |
| Coloretti et al., 2020 [22] | N = 112 T = 56 C = 56 Age (years) T = 69 (56–76) C = 69 (56–77) Male n(%) T = 37 (66.1) C = 32 (57.1) SAPS II score T = 61 (47–72) C = 56 (47–71) SOFA score T = 11 (8–12) C = 11 (8–13) Medical admission n(%) T = 36 (64.3) C = 33 (58.9) | Use of intravenous vitamin C at the dosage of 1.5 g every 6 h and thiamine at the dosage of 200 mg every 12 h up to discontinuation of vasoactive drugs or steroids. | Current sepsis management guidelines. | 30-day mortality n (%) T = 24/56 (42.8) C = 28/56 (50.0) Hospital mortality n (%) T = 28/56(50.0) C = 34/56 (60.7); Mechanical ventilation: T: 41/56; C: 48/56 Vasopressors length (days) T = 3 (2–5) C = 4 (2–7) Mechanical ventilation (days) T = 3 (0–8) C = 6 (2–15) RRT n(%) T = 22/56 (39.2) C = 21/56 (37.5) ICU LOS (days) T = 6 (4–10) C = 9 (5–15) |
| Dingchao et al., 1994 [23] | N = 85 [T = 45 C = 40] There were no significant differences in age, weight, CPB time and aortic clamping time between the two groups. | Receiving 250 mg/kg of ascorbic acid. Ascorbic acid was introduced intravenously 30 min before CPB and at the aortic decamping (125 mg/kg each time). | Standard of care without ascorbic acid. | ICU stay (hour) T = 25 ± 4.7 C = 45 ± 8.5 Hospital stay (day) T = 22 ± 4.0 C = 35 ± 5.9 |
| Du et al., 2003 [52] | N = 84 [ T = 40, C = 44] Age, mean years T = 40 ± 12 C = 43 ± 14 Gender (M/F) T= 25/15 C = 28/16 | In the treatment group, vitamin C (10 g/day) was given intravenously for 5 days, high dose. | In the control group (n = 44), vitamin C (1 g/day) was given intravenously for 5 days (Low dose). | Hospital LOS T = 9.34 ± 4.24 C = 13.45 ± 3.21 |
| Emadi et al., 2019 [45] | N = 50 [T = 25 C = 25] Age (years) T = 60 ± 6.62 C = 63.64 ± 8.26 Gender (male/female) (%) T = 72/28 C = 56/44 | Received 5 g of intravenous vitamin C before induction of anesthesia and 5 g of vitamin C in the cardioplegic solution. | Given the same amount of placebo (normal saline). | Intubation time (h) T = 10.76 ± 2.14 C = 11.72 ± 2.57 ICU stay (days) T = 1.22 ± 0.27 C = 1.58 ± 1.18 Hospital stay (days) T = 4.12 ± 0.33 C = 5.16 ± 3.44 |
| Fowler et al., 2014 [3] | N = 26 [TH = 8, TL = 8, C = 8] Gender(M/F): TH = 4/4 TL = 5/3 C = 4/4 Age, range in years TH = 49–92 TL = 30–70 C = 54–68 APACHE II score, mean (range). TH = 24.0 (12–33) TL = 20.4 (12–23) C = 20.4 (15–29) SOFA score, mean ± SE. TH = 10.8 ± 4.4 TL = 10.1 ± 2.0 C = 13.3 ± 2.9 | Low dose ascorbic acid (Lo-AscA): TL 50 mg/kg/24 h High dose ascorbic acid (Hi-AscA) TH: 200 mg/kg/24 h. Ascorbic acid dosage was divided into 4 equal doses and administered over 30 min every 6 h for 96 h in 50 mL of 5% dextrose and water. Study drug infusion was initiated 2–4 h following informed consent and randomization. | Placebo: 5% dextrose and water. | Days on Vasopressor, mean (range) TH = 3.6 (2–8); TL = 2.1 (1–6); C = 3.9 (1–10) Ventilator Free Days, mean (range) TH = 4.8 (0–19); TL = 8.4 (0–22); C = 7.6 (0–23) ICU Length of Stay, mean (range) TH = 9.1 (2–25); TL = 8.1 (1–19); C = 11.0 (2– 25) 28-Day mortality, TH = 4/8 (50.6%); TL = 3/8 (38.1%); C = 5/8 (62.5%) |
| Fowler et al., 2019 [4] | N = 167 [T = 84 C = 83] Age, median (IQR), y T = 54 (39–67) C = 57 (44–70) Gender, number (%) Men T = 45 (54) C = 45 (54) Women T = 39 (46) C = 38 (46) Incidence of shock, No. (%) At baseline, vasopressor in use T = 57 (68) C = 60 (72) SOFA scores, mean (SD) At randomization T = 9.8 (3.2) C = 10.3 (3.1) At 96 h T = 8.02 (4.2) C = 6.96 (3.5) Corticosteroid use during study, No. (%) T = 56 (67) C = 54 (65) | Vitamin C at 50 mg/kg actual body weight infused intravenously every 6 h for total 96 h in 5% dextrose in water. | Placebo (5% dextrose in water alone). | All-cause mortality in 28 days, T = 25/84 C = 38/82 The ventilator-free days T = 13.1 C = 10.6 The ICU-free days to day 28 T = 10.7 C = 7.7 Transfer out of the ICU by hour 168 or less T = 21/84 C = 10/83 The hospital-free days T = 22.6 C = 15.5 Creatinine 0 h: T = 1.1(1.3)C = 1.7(1.8)48 h: T (82) = 1.6 (1.4); C(73) = 1.2 (1.0) 96 h: T(78) = 1.1(1.1); C(65) = 1.1(0.9) 168 h: T(64) = 1.0(1.2); C(55) = 1.2 (1.6) |
| Fujii et al., 2020 [53] | N = 211 T = 107 C = 104 Age, mean (SD), y T = 61.9 (15.9) C = 61.6 (13.9) Sex, No. (%) Male n (%) T = 68 (63.6) C = 65 (62.5) Female (%) T = 39 (36.4) C = 39 (37.5) Weight, median (IQR), kg T = 81.0 (66.0–95.0) C = 83.0 (67.5–102.0) Mechanical ventilation T = 66 (61.7) C = 65 (62.5) Norepinephrine T = 99 (92.5) C = 97 (93.3) Vasopressin T = 22 (20.6) C = 22 (21.2) Epinephrine T = 13 (12.1) C = 9 (8.7) Metaraminol T = 8 (7.5) C = 10 (9.6) Inotropes Milrinone T = 6 (5.6) C = 2 (1.9) RRT T = 12 (11.2) C = 12 (11.5) AKI, No. (%)h T = 74 (69.2) C = 75 (72.1) Stage 1 (mild) T = 27 C = 32 Stage 2 (moderate) T = 34 C = 23 Stage 3 (severe) T = 13 C = 20 APACHE III score T = 77.4 (29.7) C = 83.3 (28.8) SOFA score T = 8.6 (2.7) C = 8.4 (2.7) Serum creatinine, Median (IQR), mg/dL T = 1.73 (1.16–2.64); C = 1.78 (1.07–2.90) |
IV vitamin C (1.5 g every 6 h), hydrocortisone (50 mg every 6 h) and thiamine (200 mg every 12 h). | Received IV hydrocortisone (50 mg every 6 h). | 28-d Mortality, No. (%) T = 24/106 (22.6) [n = 106] C = 21/103 (20.4) [n = 103] 90-d Mortality, No. (%) T = 30/105 (28.6) [n = 105] C = 25/102 (24.5) [n = 102] ICU mortality, No. (%) T = 21/107 (19.6) C = 19/104 (18.3) Hospital mortality, No. (%) T = 25/107 (23.4) C = 21/103 (20.4) [n = 103] 28-d Cumulative vasopressor-free days, median (IQR) T = 25.6 (17.8 to 26.8) [n = 106] C = 25.8 (19.6 to 26.8) [n = 103] 28-d Cumulative MV-free days, median (IQR) T = 25.3 (5.2 to 28.0) [n = 106] C = 24.8 (9.5 to 28.0) [n = 103] 28-d RRT–free days, T = 28.0 (23.5 to 28.0) [n = 105] C = 28.0 (21.0 to 28.0) [n = 103] 28-d ICU-free days, T = 21.9 (0 to 25.8) [n = 106] C = 22.1 (3.9 to 25.8) [n = 103] Hospital LOS, d T = 12.3 (6.2 to 26.0) [n = 106] C = 12.3 (6.2 to 26.1) [n = 103] AKI (1,2,3) T = 75/107, C = 75/104 Stage 1 T = 18/107 (16.8) C = 14/104 (13.5) Stage 2 T = 18/107 (16.8) C = 22/104 (21.2) Stage 3 T = 39/107 (36.4) C = 39/104 (37.5) |
| Giladi et al., 2011 [24] | N = 4294 T = 2272 C = 2022 Male n (%) T = 1832 (81%) C = 1452 (72%) White race n (%) T = 1291 (79%) C = 1587 (78%) Mean age, years (SD) T = 40 ± 17 C = 39 ± 18 Mean admission GCS (SD) T = 12 ± 5 C = 13 ± 4 Mean ISS (SD) T = 20 ± 12.3 C = 21 ± 12.6 Mean predicted survival(SD) by TRISS methodology T = 0.822 ± 0.285 C = 0.885 ± 0.222 Renal failure, n (%) T = 30/2272 (1.3%) C = 26/2022 (1.3%) |
Intravenous ascorbic acid 1000 mg intravenously in 100 mL of NS every 8 h, alpha-tocopherol 1000 IU (1 mL) via naso- or orogastric tube every 8 h, and selenium 200 mcg intravenously in 100 mL NS once daily. Ascorbic acid was administered as a bolus over 1 h and selenium as a bolus over 2 h, although both were permitted to be changed to an enteral dosage form once enteral access was established. The treatment course was 7 days or until discharge from hospital, whichever came first. | No antioxidants, only standard of care. | Mortality: T = 139/2272(6.1%) C = 172/2022(8.5%) ICU-LOS days, (IQR) T = 2 (1–4) C = 3 (1–6) Hospital LOS, days,(IQR) T = 3 (1–6) C = 4 (2–8). Ventilator free days (IQR) T = 3 (1–6) C = 3 (1–6). Respiratory failure, n (%) T = 395/2272 (17.4%) C = 558/2022 (27.6%) Ventilator-dependent respiratory failure, n (%) T = 160/2272 (7.1%) C = 218/2022 (10.8%) Renal failure, n (%) T = 30/2272 (1.3%) C = 26/2022 (1.3%) SIRS, n (%) T = 360/2272 (15.0%) C = 283/2022 (13.8%) ICU subset analysis Hospital stay T = 8.8 days C = 10.6 days ICU stay T = 3.9 days C = 4.9 days |
| Hwang et al., 2020 [49] | N = 111 T = 53 C = 58 Age (years) T = 70 (62–76)C = 69 (62–74) Sex (male) T = 20 (37.7) C = 22 (37.9) Chronic renal disease T = 3 (5.7) C = 0 (0) SOFA score T = 8 (6–10) C = 8 (6–10) APACHE II score T = 22 (14–32) C = 22 (17–32) Acute kidney injury Stage 1 T = 13/53 (24.5) C = 15/58 (25.9) Stage 2 T = 13/53 (24.5) C = 17/58 (29.3) Stage 3 T = 15/53 (28.3) C = 13/58 (22.4) Mechanical ventilation at enrolment T = 12 (22.6) C = 14 (24.1) |
Vitamin C (50 mg/kg, maximum single dose 3 g, daily dose 6 g) and thiamine (200 mg) were mixed in a 50-milliliter 0.9% saline bag, respectively, and intravenously administered to patients over 60 min every 12 h for a total of 48 h. | Identical volume of 0.9% saline from the placebo drug ampoule was administered to patients using the same protocol. | 7-day mortality T = 5/53 (9.4) C = 6/58 (10.3) 28-day mortality T = 11/53 (20.8) C = 9/58 (15.5) 90-day mortality T = 17/53 (32.1) C = 16/58 (27.6) In-hospital mortality T = 13/53 (24.5) C = 11/58 (19) ICU mortality T = 7/46 (15.2) C = 7/52 (13.5) Shock reversal T = 44/53 (83) C = 49 /58(84.5) Vasopressor-free days T = 11 (5–12) C = 11 (10–12) Mechanical ventilation (days) T = 6 (3–12) [n = 23] C = 7 (3–8) [n = 24] Ventilator-free days T = 11 (2–14) C = 11 (3–14) New use of RRT T = 9/52 (17.3) C = 11/58 (19) RRT-free days T = 14 (14–14) [n = 52] C = 14 (14–14) [n = 58] ICU LOS (day) T = 5 (3–11) [n = 46] C = 5.5 (4–12.5) [n = 52] ICU-free days T = 9 (3–11) C = 9 (0–11) Hospital LOS (day) T = 14 (11–21) C = 13.5 (9–26) |
| Iglesias et al., 2020 [54] | Total patients (N) = 137 T = 68 C = 69 Age T = 70 ± 12 C = 67 ± 14 Sex (male) T = 32 (47%) C = 27 (39%) ESRD T = 3 (0.4%) C = 0 (0%) CKD T = 10 (7%) C = 4 (2.9%) Mechanical ventilation T = 34 (50%) C = 35 (51%) Vasopressors T = 56 (82%) C = 47 (68%) AKI T = 54 (79%) C = 52 (75%) Day 1 SOFA T = 8.3 ± 3 C = 7.9 ± 3.5 APACHE II T = 24 ± 7.6 C = 24.9 ± 8.7 APACHE IV T = 88 ± 28.3 C = 87.5 ± 29.7 | Ascorbic acid 1500 mg q 6 h, thiamine 200 mg every 12 h and hydrocortisone 50 mg q6 h. | A matching saline placebo for a maximum of 4 days. | Days of HAT therapy or placebo T = 3.3 ± 0.8 C = 3.25± 1 Vasopressor after study enrollment T = 4 (6%) C = 10 (14.5%) RRT for AKI T = 2/68 (3%) C = 8/69 (11.5%) ΔSOFA score at 72 h T = 2.9 ± 3.3 C = 1.93 ± 3.5 Duration of vasopressors, h T = 27 ± 22 C = 53 ± 38 Hospital mortality (%) T = 11/68 (16%) C = 13/69 (19.4%) ICU mortality (%) T = 6/68 (9%) C = 10/69 (14%) Hospital LOS, d T = 11.5 ± 6.8 C = 11 ± 6.2 ICU LOS, d T = 4.76 ± 4.3 C = 4.66 ± 3.45 Ventilator-free days T = 22 ± 6.2 C = 22.4 ± 4.3 AKI T = 54/68 (79%) C = 52/69 (75%) (Serum creatinine (mg/dL) SCr 24 h T = 1.74± 1.21 C = 1.85 ± 1.6 SCr 48 h T = 1.62± 1.32 C = 1.8± 1.71 SCr 72 h T = 1.47± 1.3 C = 1.67 ± 1.71 SCr at discharge T = 1.32± 1.13 C = 1.37± 1.18 |
| Kahn et al., 2011 [25] | N = 33 [T = 17, C = 16] Age (yr) T = 42 ± 16 C = 50 ± 20 Male T = 16 C = 16 APACHE II T = 17 ±7 C = 18 ±8 Inhalation: T = 4 C = 4 |
LR based on Parkland formula with 66 mg/kg/hr VC administered during resuscitation until the patient was down to maintenance fluid (approximately 24 h). | LR solution only according to the Parkland formula. | Mortality T = 4/17 C = 3/16 Need of vasopressors, mean hours T = 6 ± 9, C = 11 ± 10 Renal failure: T = 2/17 C = 2/16 Pneumonia: T = 7/17 C = 10/16 Fasciotomy: T = 3/17 C = 3/16 |
| Kim et al., 2018 [26] | N = 99 T = 53 C = 46 Male: T = 41 (77) C = 29 (63) Chronic kidney disease: T = 8 (15) C = 8 (17) ARDS at ICU admission T = 12 (23) C = 10 (22) APACHE II score at ICU admission T = 28 (21−32) C = 27 (22−32) SOFA score at ICU admission T = 11 (8–14) C = 11 (7–12) Use of MV in 1st day T = 43 (81) C = 36 (78) Vasopressor use in 1st day T = 33 (62) C = 22 (48) Use of RRT in 1st day T = 19 (36) C = 5 (11) Creatinine, mg/dL T = 1.1 (0.7–1.9) C = 0.8 (0.6–1.6) |
Treatment group was treated with vitamin C protocol. The protocol consisted of intravenous vitamin C (1.5 g every 6 h for 4 days), hydrocortisone (50 mg every 6 h for 7 days followed by a taper over 3 days) and intravenous thiamine (200 mg every 12 h for 4 days). Treatment group was administered 6 g of vitamin C per day (divided into four equal doses). | The patients who were admitted to the same ICU between June 2016 and January 2017 were not treated with the vitamin C protocol and thus formed the control group. | At 28-day vasopressor-free days; T:18.8 ± 11.2, C: 19.6 ± 11.4 At 28-day ventilator-free days T: 10.7 ± 10.8, C:9.7 ± 10.9 ICU stay, d T:9 (4–14); C:12 (6–17) Hospital mortality: T:11/53 (21); C:17/46 (37) Among PPM cohort (T = 36, C = 36) At 28-day vasopressor-free; T = 19.8 ± 10.8, C = 20.5 ± 11.1 At 28-day ventilator-free days; T = 12.3 ± 11.0, C = 9.9 ± 10.7ICU stay, d T = 9 (5–14) C = 12 (7–17) Hospital mortality T = 6 (17) C = 14 (39) |
| Lin et al., 2018 [27] | N = 80 T = 38 C = 42 Age T = 41 ± 15 C = 42.4 ± 17 Inhalation injury T = 52% C = 36% Admission BUN (mg/dL) T = 12 (7–17) C = 12 (9–15) Admission Cr (mg/dL) T = 1.18 ± 0.6 C = 1.26 ± 0.5 mg/d |
High dose ascorbic acid was started for Burn Shock Resuscitation at a dose of 66 mg/kg/hr, along with BSR based on Parkland formula calculations and received lactated Ringers for resuscitation. | Burn shock resuscitation (BSR) based on Parkland formula calculations and received lactated Ringers for resuscitation. | Mortality T = 10/38(26%) C = 10/42(24%) Ventilator days T = 11 (6–28) C = 5.5 (1–22) Hospital LOS (days) T = 29 (18–57) C = 24.5 (14–46) Abdominal Compartment Syndrome (ACS) T = 2/38 (5.2%) C = 1/42 (2.3%) AKI T = 9/38 (23%) C = 3/42 (7%) Ventilator-Associated Pneumonia (VAP) T = 11/38 (29%) C = 6/42 (14%) day 1 BUN (mg/dL) T = 12 (7–15) C = 12 (6–17) day 1 Cr (mg/dL) T = 1.26 ± 0.6 C = 1.42 ± 0.5 mg/d |
| Litwak et al., 2019 [28] | N = 94 (T = 47 C = 47) Age, mean SD, year T = 58.3 ±17.0 C= 60.1 ±14.0 Sex, male, No (%) T = 28 (59.6) C = 29 (61.7) CKD T = 4 (8.5) C = 10 (21.3) Mechanical ventilation, No (%) T = 43 (91.5) C = 39 (83.0) Vasopressors, No (%) T = 47 (100) C = 47 (100) AKI, No (%) T = 38 (80.9) C = 32 (68.1) Day 1 SOFA, mean SD T = 10.6 ± 10.6 C= 9.7 ± 10.0 APACHE II, mean SD T = 21.5± 8.0 C = 20.0 ±7.4 APACHE IV, T = 88.6 ± 29.1 C = 84.1 ± 25.4 Creatinine, median (IQR), mg/dL (excluding CKD) T = 1.4 (0.9–2.2) C = 1.4 (0.9–2.5) | At least one dose of each of the following medications intravenously: 1.5 g vitamin C every 6 h, 200–300 mg hydrocortisone daily (50 mg every 6 h or 100 mg every 8 h) and thiamine 200 mg every 12 h. | Standard of care but could receive hydrocortisone. | Hospital mortality T = 19/47 C = 19/47 ICU mortality T = 17/47 C = 18/47 RRT for AKI T= 11 of 38 C = 11 of 32 ICU LOS, days T = 11.0 (7.0–19.0) C = 10.0(5.0–17.0) Hospital LOS, days T = 19.0(9.0–26.0) C = 14.0 (8.0–23.0) Vasopressors, hours T = 84.2(37.0–169.3) C = 62.5(32.6–105.9) Change in SOFA score in 72 h, mean ± SD T = 1.3 ± 4.1 C= 0.1 ± 4.7 Sub group analysis Hospital mortality T = 7/20 C = 19/47 ICU mortality T = 6/20 C = 18/47 RRT for AKI T = 5 of 16 C= 11 of 32 ICU LOS days T = 14.5(7.5–22.0) C = 10.0 (5.0–17.0) Hospital LOS, days T = 19.0(9.3–23.5) C = 14.0(8.0–23.0) |
| Long et al., 2020 [29] | N = 206 T = 79 C = 127 Age, Yrs (mean, SD) T = 64.4 (13.9) C = 61.1 (16.2) Male gender n,% T = 43 (54.4) C = 71 (55.9) ESRD T = 5/79 (6.3) C = 17/127(13.4) Ventilator initiation, n, % T = 33 (41.7) C = 71 (55.9) Hydrocortisone use, n,% T = 79(100) C= 40 (31.5) | Hydrocortisone 50 mg IV every 6 h, vitamin C in a dose of 1.5 g IV every 6 h and thiamine 200 mg IV every 12 h, until the patient was either liberated from vasopressors, was discharged from the ICU or until 4 days of therapy had elapsed, whichever came first. | Standard of care: Surviving Sepsis Campaign Guidelines. | APACHE IV score T = 80.0 C = 88.2Observed ICU mortality, N (%) T = 9/79 (11.4) C = 33/127 (26.0) Hospital mortality T = 21/79 (26.6) C = 41/127 (32.3) Vasopressor duration, hours(median)T = 13.9 C = 24.2 New RRT initiation n (%)T = 11/74 (14.9%) C = 29/110 (26.4%) Ventilator duration days T = 3.4 C = 3.3 ICU LOS, days(median) T = 2.0 C = 2.5 Hospital LOS, days(median)T = 9.5 C = 9.1 |
| Lv et al., 2020 [55] | N = 117 T = 61 C = 56 Sex, male, n (%) T = 30 (49.2) C = 29 (51.8) Age, mean ± SD, T = 58.7 ± 14.3 C = 60.2 ± 14.1 CRF, n (%) T = 3 (4.9) C = 4 (7.1) Ventilator, n (%) T = 31 (50.8) C = 28 (50.0) Vasoactive drugs, n (%) T = 35 (57.4) C = 33 (58.9) AKI, n (%)T = 29/61 (47.5) C = 27/56 (48.2) APACHE II, Median [IQR] T = 21.0 (19.0, 28.0) C = 23.0 (20.0, 29.0) Day 1 SOFA, mean ± SD T = 8.6 ± 2.9 C = 8.9 ± 3.1 | Vitamin C from the day of entering ICU, administered intravenously by 3.0 g of vitamin C dissolved into 5% dextrose (100 mL/time, 2 times/day) until ICU discharge. | Intravenously by 5% dextrose (100 mL/time, 2 times/day) as placebo. | 28-day mortality (%) T = 15/61 (24.6) C = 24/56 (42.9) ICU stay, day, Median [IQR] T = 4.1 (3.2, 8.3) C = 3.9 (3.1, 7.5) SOFA after72 h Median [IQR] T = 4.2 (1.2, 6.6) C = 2.1 (1.1, 4.3) Application time of vasoactive drugs [h, (IQR)] T = 25.6 (18.8, 40.6) C = 43.8 (24.7, 66.8) |
| Marik 2017 [5] | N = 94 [T = 47 C = 47] Sex, male, n T = 27 C = 23 Ventilation, N (%) T = 22 (47) C = 26 (55) Vasopressors, N (%) T= 22 (46) C = 22 (46) AKI, N (%)T = 31/47 (66) C = 30/47 (64) Day 1 SOFA, mean ± SD; T = 8.3 ± 2.8 C = 8.7 ± 3.7 APACHE II, mean ± SD; T= 22.1 ± 6.3 C = 22.6 ± 5.7; CRF T = 7/47 (15) C = 8/47 (17) Creatinine mean ±SD, mg/dL T = 1.9 ± 1.4 C = 1.9 ± 1.1 | Intravenous vitamin C (1.5 g every 6 h for 4 days or until ICU discharge), hydrocortisone (50 mg every 6 h for 7 days or until ICU discharge followed by a taper over 3 days), as well as intravenous thiamine (200 mg every 12 h for 4 days or until ICU discharge). | Patients received hydrocortisone (50 mg every 6 h) at the discretion of the attending physician and all standard of care. | Hospital mortality, N; T = 4/47 C= 19/47 ICU LOS, median and IQR, d T = 4 (3–5) C = 4 (4–10) Vasopressors, mean ± SD, h T= 18.3 ± 9.8 C = 54.9 ± 28.4 Change in SOFA, 72 h T = 4.8 ± 2.4 C = 0.9 ± 2.7 RRT for AKI, No. (%) T = 3/31 (10%) C = 11/30 (33%) |
| Masood et al., 2019 [30] | N = 50 Mean age: 46.7 ± 18.4 (range: 16 to 77 years old) Gender: Male 28 (56); Female 22 (44) | IV thiamine 200 mg BD for 5 days along with IV vitamin C 1500 mg QID and IV hydrocortisone 50 mg QID for 5 days. | - | Median days in ICU= 8.3 [IQR = 5] Mortality, N = 24/50 (48%) SOFA score= 8.5 ± 1.5 Duration of vasopressor support < 24 h = 29 (58%) 24–48 h = 13 (26%) |
| Matsuoka et al., 2020 [31] | N = 17 T = 6 C = 11 Age (years) T = 67.7 ± 1.4 C = 69.7 ± 2.3 Male N (%) T = 4 (67) C = 10 (91) Both group received Methyl-prednisolone | Received ascorbic acid (1.5 g) and thiamine (200 mg) as per protocol. | Standard postoperative management. | Ventilation (days): T = 2.0 ± 0.0; C = 4.2 ± 0.3 ICU LOS (days): T = 3.2 ± 0.3; C = 6.9 ± 0.9 ARDS: T = 0 (0) C = 1 (9) Pneumonia T = 2 (33) C = 5 (45) |
| Mirmohammadsadeghi et al., 2018 [56] | N = 314 T = 160 C = 154 Age (mean years) T = 62.1 C = 62.7 Age >70 years T = 5 C = 6 Gender (male) T = 128 C = 116 | 2 g of vitamin C intravenously (IV) 24 h preoperatively, and postoperatively 500 mg every 12 h IV for 48 h in ICU, and 500 mg every 12 h PO for 48 h in ward. | Standard of care. | Postoperative stroke (%) T = 3/160 (1.9) C = 1/154 (0.7) Postoperative TIA (%) T = 0/160 (0) C = 2/154 (1.3) ICU stay (hours) T = 50.4 C = 52.5 Hospital stay (days) T = 8.13 C = 8.22 Atrial fibrillation (patients) T = 12/160 C = 12/154 Inotrope dependent T = 37/160 C = 39/154 |
| Mitchell et al., 2019 [32] | N = 76 T = 38 C = 38 Mean age, years ± SD T = 68 ± 10 C = 68 ± 10 Male, n (%) T = 36 (95) C = 37 (97) Mean SOFA score ± SD T = 6.9 ± 4 C = 6 ± 3 Need for vasopressors, n (%) T = 30 (79) C = 29 (76 Ventilation, n (%) T = 19 (50) C = 17 (45) CKD/ESRD T = 9/38 (24) C = 8/38 (21) |
Vitamin C was administered at a dose of 1.5 g IV every 6 h and thiamine 200 mg IV every 12 h for 4 days in addition to hydrocortisone. | IV prednisolone alone. | ICU mortality n (%) T = 12/38 (32) C = 13/38 (34) Hospital mortality n (%) T = 18/38 (47) C = 20/38 (53) 28 day Mortality n (%) T = 22/38 (58) C = 23/38 (61) 60 day Mortality n (%) T = 22/38 (58) C = 25/38 (66) AKI requiring RRT, n (%) T = 6/38 (16) C = 7/38 (18) Vasopressor duration, days T = 2.5 C = 4.8 Hospital LOS, days T = 20 C = 32.6 ICU LOS, days T = 7.1 C = 15.6 |
| Mohamed et al., 2020 [57] | N = 88 T = 45 C = 43 Age, mean T = 58.69 ± 14.89 C = 59.37 ± 15.01 Male T = 31 (69) C = 32 (74) CKD T = 6 (14) C = 11 (25) GCS T = 15 (2–15) C = 15 (2–15) SOFA T = 11.22 ± 2.99 C = 10.89 ± 3.82 Creatinine (mg/dL) T = 2.8 ± 1.6 C = 2.5 ± 1.9 |
Intravenous hydrocortisone (50 mg every 6 h), vitamin C (AA) (1.5 g every 6 h) and thiamine (200 mg every 12 h) for 4 days. | Standard of care for septic shock. | Mortality (%) T = 26/45 (57) C = 23/43 (53) Reversal shock (hrs) T = 34.58 ± 22.63 C = 45.42 ± 24.4 Mechanical ventilation T = 22 (48.8) C = 20 (46.5) SOFA at 72 h T = 8.9 ± 3.6 C = 9.3 ± 3.8 Change in SOFA T = 2.23 ± 2.4 C = 1.38 ± 3.1 New onset of AKI T = 7/45 (15) C = 5/43 (12) ICU LOS T = 12.44 ± 14.2 C = 8.44 ± 8.16 Hospital LOS T = 31.58 ± 31.06 C = 20.9 ± 15.01 |
| Moskowitz et al., 2020 [58] | N = 200 T= 101 C= 99 Age, mean y, (SD) T = 68.9 (15.0) C = 67.7 (13.9) Sex, Female T = 44 (43.6) C = 45 (45.5) Chronic kidney disease stage 2 (Mild) T = 1 (1.0) C = 1 (1.0) 3 (Moderate) T = 4 (4.0) C = 6 (6.1) 4 (Severe) T = 2 (2.0) C = 3 (3.0) Unknown 3 (3.0)3 (3.0) SOFA mean (SD) T = 9.1 (3.5) C= 9.2 (3.2) Ventilation, No. (%) T = 48 (47.5) C = 44 (44.4) | Ascorbic acid (1500 mg), hydrocortisone (50 mg) and thiamine (100mg) every 6 h for 4 days or until intensive care unit (ICU) discharge. Hydrocortisone was administered intravenously as a push dose in 1 mL of saline over 1 to 2 min. | 0.9% sodium chloride in a matching volume (approximately 100 mL) using the same techniques at the same time points. | SOFA score at 72 h, mean (SD): T = 4.4 (4.1) [n = 90] C = 5.1 (4.3) [n = 88] 30 d, Mortality n (%) T = 35/101 (34.7) C = 29/99 (29.3) AKI n (%) T = 32/101(31.7) C = 27/99 (27.3) Ventilator-free days, median (IQR) T = 6 (2–7) C = 6 (0–7) Shock-free days, median (IQR) T = 5 (3–5) C = 4 (1–5) Incidence of delirium, No./total (%) T = 31/83 (37.4) C = 35/76 (46.1) ICU-free days, median (IQR) T = 22 (3–25) C = 21 (4–25) |
| Nagel et al., 2020 [33] | N = 38 T = 19 C = 19 Age (years) T = 47 ± 18.8 C = 49 ± 17.9 Gender (female:male) T = 6 13 C = 6:13 ABSI(abbreviated burn severity index) T = 7 (5–12) C = 7 (4–12) Admission Crea (mg/dL): T = 0.99 ± 0.34 C= 1.14 ± 0.64 |
High dose ascorbic acid was infused continuously over 24 h with 66 mg/kg per hour intravenously. | Low dose ascorbic acid 3.5 g as a single infusion. | Mortality (%) T (HDAA) = 5/19 (26.3) C (LDAA) = 2/19 (10.5) 24-hr Vasopressor use (%) T = 5/19 (26.3) C = 8/19(42.1) 24–72 hrs Vasopressor use T = 5/19(26.3); C = 10/19 (52.6) Hospital LOS (d) T = 39 ± 33 C = 58 ± 46 Pneumonia (%) T = 2/19 (10.5) C = 2/19(10.5) Ventilation (d) T = 19.5 ± 26.0 C = 10.1 ± 20.9 AKI (AKIN 1, 2, 3): T = 15/19; C = 13/18 RRT (%) T = 4/19 (21.0) C = 3/19 (15.8) 24-hr Crea (mg/dL): T = 1.85 ± 0.9 C = 1.67 ± 1.18 72-hr Crea (mg/dL): T = 1.27 ± 0.76 C = 1.32 ± 1.23 |
| Nakajima et al., 2019 [7] | Before PSM N = 2713 T = 157 C = 2556 Age (years), median (IQR) T = 67 (48–80) C = 69 (51–80) Male, n (%) T = 87 (55.4) C = 1561 (61.1) Inhalation injury, n (%) T = 45 (28.7) C = 523 (20.5) After PSM N = 785 T = 157 C = 628 Age(years), median (IQR) T = 67 (48–80) C = 67.5 (50–80) Male n(%) T = 87 (55.4) C = 332 (52.9) Inhalation injury n (%) T = 45 (28.7) C = 181 (28.8) | High dose vitamin C was administered under the following two varying thresholds: dosage more than (1) 10 g within 2 days of admission and (2) 24 g within 2 days of admission. High-dose vitamin C administered as a continuous intravenous infusion during the initial 24 h period after admission. | Standard of care. | In hospital mortality 10 g threshold of high dose Vitamin C T = 72/157 C = 364/628 24 g threshold of high dose Vitamin C T = 58/127 C = 278/508 |
| Nathens et al., 2002 [59] | N = 595 T = 301 C = 294 Age (mean± SD) T = 38± 15 C = 39 ± 15 Gender Male T = 230 (76) C = 222 (76) Illness severity ISS (mean ±SD) T = 19.1± 10 C = 20 ± 11 APACHE II (mean ±SD) T = 13.6± 6 C = 14.3± 6 | Alpha-tocopherol 1000 IU (20 mL) q8h per naso- or orogastric tube and 1000 mg ascorbic acid given intravenously in 100 mL of D5W q8h for the shorter duration of admission to the ICU or 28 days. | Standard of care. | Duration of ventilation (mean days) T = 3.7 C = 4.6 Ventilator-free days (mean) T = 24.1 C = 23.3 Multiple organ dysfunction score (mean) T = 2.4 C = 3.2 ICU length of stay, days (mean) T = 5.3 C = 6.4 Hospital length of stay (mean) T = 14.6 C = 15.1 Multiple organ failure T = 8/301 (2.7%) C = 18/294 (6.1%) Mortality 28-day T = 4/301 (1.3%) C = 7/294 (2.4%) ICU T = 3/301 (1.0%) C = 9/294 (3.1%) Hospital T = 5/301 (1.7%) C = 9/294 (3.1%) |
| Palli et al., 2017 [60] | N = 124 [T = 60 C = 64] Age (yrs) T= 51.34 (2.71) C = 50.51 (2.65) Male n (%) T = 46 (76.66) C = 55 (85.93) APACHE II score T = 14.44 (1.01) C = 13.29 (0.78) SOFA score T = 5.94 (0.5) C = 6.14 (0.41)Ventilator T= 32/60 (53.33) C = 44/64 (68.75) Vasoactive therapy, n (%) T = 20/60 (33.33) C = 25/64 (39.06) | Intravenously receive NAC (1200 mg) and ascorbic acid (2 g) dissolved separately in 100 mL of normal saline (N/S) 0.9%, 2 h before and at 10 h and 18 h following the infusion of contrast agent. | 200 mL of intravenous N/S 0.9%. | ICU LOS (days, median) T = 32.5 (5.11) C = 27.5 (4.49) ICU mortality, n (%) T = 15/60 (25) C = 11/64 (17.18) RRT 10 days post contrast agent, n (%) T = 3/60 (5) C = 4/64 (6.25) |
| Park et al., 2020 [34] | Before Matching N = 435(T = 94, C = 341) Male [T = 55 (58.5), C = 229 (67.1)] Age: T = 69 (60–76), C = 69 (61–76) CKD T = 7/94 (7.5) C = 23/341 (10.3) Creatinine (mg/dL) T = 2.1 ± 1.5 C = 1.8 ± 1.6 APACHE II score T = 30.2 ± 8.1 C = 28.4 ± 9.2 SOFA score T = 11.5 ±3.4 C = 10.1 ± 3.7 Mechanical ventilation, T = 53 (56.4) C = 173 (50.7) After Matching N = 178(T = 89, C = 89) Male: [T = 52 (58.4) C = 55 (61.8)] Age: T = 69 (61–76), C = 71 (62–78) CKD T = 7/89 (7.8) C = 9/89 (10.1) Creatinine (mg/dL) T = 1.9 ± 1.4 C = 2.2 ± 2.3 APACHE II score T = 30.0 ± 7.9 C = 30.0 ± 8.9 SOFA score T = 11.4 ± 3.5 C = 11.5 ± 3.4 Mechanical ventilation, T = 49 (55.1) C = 48 (53.9) |
Vitamin C (3 g/12 h or 1.5 g/6 h) and thiamine (200 mg/12 h) mixed in 50- or 100-milliliter solution bags of 5% dextrose in water or normal saline were administered intravenously within 6 h of shock recognition. | Protocol-driven therapies based on the updated Surviving Sepsis Campaign guidelines were provided for all included patients. |
Before Matching Delirium free days T= 11 C = 13 Delirium coma free days T = 13 C = 11 Incidence of delirium = 62/94 C = 194/341 Duration of delirium, days T= 2 C = 1 Hospital stay, days T = 16 C = 13 ICU stay, days T = 4 C= 4 28-day mortality T = 23/94 C = 72/341 Among matched cohort Delirium free days T = 11 C = 12 Delirium coma free days T = 11 C= 12 Incidence of delirium T = 57/89 C = 54/89 Hospital stay days median (IQRs) T = 16 (8–27); C= 13 (7–28) ICU stay days T= 4 (3–7); C= 4 (3–7) 28-day mortality T= 21/89; C= 16/89 |
| Reddy et al., 2020 [61] | N = 19 [T1 = 7 T2 = 5 C = 7] Age mean (SD) T1 = 56.5 (12) T2 = 53.8 (11) C = 55.4 (12.3) Male T1= 3 (15.7) T2 = 4 (21) C = 3 (15.7) APACHE score, mean (SD) T1= 17 (3.8) T2 = 18.4 (2.5) C = 21.2 (6.5) SOFA score, mean (SD) T1 = 11 (3.4) T2 = 9.2 (0.4) C = 8.8 (2.9) | T1 (hydrocortisone + vitamin C)- Hydrocortisone 200 mg over 24 h infusion and ascorbic acid in dose of 1.5 g IV every 6 h T2 (hydrocortisone + vitamin C + thiamine)- Hydrocortisone 200 mg over a 24-hour infusion, ascorbic acid in dose of 1.5 g IV every 6 h and thiamine dose of 200 mg IV every 12 h | Hydrocortisone was administered as 200 mg over a 24-hour infusion only. | Time to shock reversal (minutes), mean (SD) T1(7) = 2525 (3086); T2 (5) = 1860 (749); C(5) = 7422 (8348) Time to vasopressor reduction (minutes) from SOFA (h) 4–3 mean (SD) T1 (5) = 2310 (2515); T2 (5) = 1800 (1282); C (6) = 4935 (6406) |
| Sadaka et al., 2020 [35] | N = 62; T = 31, C = 31 Age, years (SD) T = 67 (16) C = 70 (12) Male, n (%) T = 16 (52) C = 16 (52) APACHE III score (SD) T = 95 (30) C = 96 (29) Mechanical ventilation, n (%) T = 27 (87) C = 27 (87) Creatinine (SD) T = 2.6 (2.4) C = 2.4 (1.9) |
Intravenous (IV) ascorbic acid (1.5 g every 6 h for 4 days), hydrocortisone (50 mg every 6 h for 7 days) and thiamine (200 mg every 12 h for 4 days). | Patients were managed as per sepsis management guidelines. | ICU mortality, n (%) T = 3/31 (9.6) C = 13/31 (42.0) Hospital mortality, n (%) T = 9/31 (29) C = 14/31 (45) ICU LOS, days, median (IQR) T = 6.4 (1.2–9.6) C = 4.0 (2.5–9.2) LOHS, days, median (IQR) T = 15.0 (10.0–22.0) C = 9.3 (3.7–19.5) RRT for AKI, n (%) T = 8/31 (26) C = 9/31 (29) Duration of Vasopressors, days, media (IQR) T = 4.5 (4.0–6.0) C = 2.0 (1.0–3.0) Ventilation-free days, median (IQR) T = 10.2 (5.0–15.0) C = 10.2 (1.6–18.0) |
| Sadeghpour et al., 2015 [62] | N = 290; T = 113, C = 177 Age, y T = 57.28 ± 14.09 C = 54.22 ± 14.39 Male T = 80 (70.8) C = 111 (62.7) Intubation time, h T = 11.83 ± 3.91 C = 14.14 ± 9.52 | A total of 2 g of vitamin C intravenously, immediately before surgery in the operating theatre, followed by 1 g daily oral doses of the tablets for the first four postoperative days. | Equal number of identical placebo tablets. | ICU Stay T = 3.42 ± 1.06 C = 3.43 ± 1.09 Hospital Stay T = 10.17 ± 4.63 C = 12 ± 4.51 Death, Impaired Renal Function and Infection T = 4/113 (3.54) C = 18/177 (10.2) |
| Sandesc et al., 2018 [36] | N = 67; T = 35 C = 32 Age (yrs), mean (SD) T = 45.62 (16.88) C = 42.67 (16.72) Gender (male), % (n) T = 74.28 (26) C = 75 (24) APACHE II, mean (SD) T = 11.74 (7.11) C = 12.09 (15.94) Lac (mmol/mL) T = 4.89 (1.99) C = 5.1 (2.5) | Antioxidant therapy included continuous intravenous sodium ascorbate 3000 mg/24 h and N-acetylcysteine 1200 mg/24 h. | Antioxidant Therapy. |
Sepsis, n (%) T = 13/35 (37.14) C = 28/32 (88.75) MODS, n (%) T = 8/35 (22.85) C = 21/32 (65.62) Mechanical ventilation > 96 h, n (%) T = 19/35 (54.28) C = 17/32 (53.21) ICU LOS, mean (SD) T = 14.4 (16.02) C = 18.25 (32.55) LOHS days, T = 26.03 (20.47) C = 38.68 (40.17) Mortality, n (%) T = 5/35 (14.28) C = 11/32 (33.6) |
| Shin et al., 2019 [37] | N:1144 T:229 C:915 Age N:67 (58–75) T:67 (58–76) C:67 (60–75) Male N:713 (62.3) T:136 (59.4) C:577 (63.1) CKD N:78 (6.8) T:15 (6.6) C:63 (6.9) Vasopressor use N:966 (84.4) T:217 (94.8) C:749 (81.9) Mechanical ventilation N:328 (17.9) T:67 (39.3) C:261 (28.5) SOFA in 24 h N:8 (5–11) T:9 (6–12) C:8 (5–11) APACHE II N:20 (15–27) T:27 (21–52) C:27 (20–56) | Within 6 h of shock recognition, vitamin C and thiamine were mixed in 50- or 100-milliliter solution bags of 5% dextrose in water or normal saline and intravenously administered for 1 day (vitamin C, 3 g/12 h or 1.5 g/6 h; thiamine, 200 mg/12 h). | All patients with septic shock were treated with protocol-driven resuscitation bundle therapy based on the Surviving Sepsis Campaign guidelines. | Overall Cohort 28-day mortality: T: 42/229 (18.3); C:160/915 (17.5) In-hospital mortality: T:38/229 (16.6); C:167/915 (18.3) ICU stay (days) T:4 (3–8); C:4 (3–8) Hospital stay (days); T:14 (9–22); C:13 (8–23) Ventilation T:6.0(3.0–15.0); C:6.0(3.0–12.0) New use of RRT T:28 (12.3); C:106 (11.9) Propensity-Matched Cohort (T:227, C:527 28-day mortality T:42/227 (18.5); C:92/527 (17.5) In-hospital mortality: T:38/227 (16.7); C:97/527 (18.4) ICU stay (days) T:4 (3–8); C:4 (3–7) Hospital stay (days) T:14 (9–22); C:13 (8–23) Ventilation T:5.5 (3.0–15.0); C:5.0 (3.0–10.0) New use of RRT T = 28/227 (12.4) C = 66/527 (12.9) |
| Siriwardena et al., 2007 [63] | N = 43 T = 22 C = 21 Age (SD) T = 64 (13) C = 71 (14) Sex (% male) T = 8(36%) C = 7(33%) APACHE admission (SD) T = 10.5 (3.4) C = 11.0 (3.5) MODS at admission (IQR) T = 1.36(0–2) C = 1.19 (0–2) | Selenium in 50 mL of normal saline, ascorbic acid in 100 mL of normal saline and n-Acetylcysteine as per protocol. | Maximal conventional therapy plus intravenous placebo for 7 days. | Organ dysfunction (day 7) Organ dysfunction (%) T = 7/22 (32) C = 4/21 (19) APACHE (SD) T = 5.73 (3.28) C = 5.33 (1.06) Renal dysfunction (%) T = 11/22 (50) C = 7/21 (33) LOHS (days)T = 20.4 (24.4) C = 14.3 (15.7) Days in ICU T = 4.0 (10.3) C = 0.0 (0.0) All-cause mortality T = 4/22 (18.2%) C = 0/21 (0.0%) |
| Vail et al., 2020 [38] | N = 338,597, T = 3574; C = 335,023 Female, N (%) T = 1671 (46.8) C = 163,190 (48.7) Age, mean ±SD, years T = 64.6 ± 14.8 C = 66.1 ± 14.7 RRT at admission, N (%) T = 999 (28.0) C = 52,015 (15.5) |
At least one charge for high-dose IV ascorbic acid (one or more vials totaling ≥500 mg in one calendar day) and at least one charge for both IV hydrocortisone and IV thiamine (of any dose) on or within one day of ascorbic acid administration | Routine treatment of septic shock without hydrocortisone, ascorbic acid or thiamine. | LOHS, median (IQR), days Survivors T = 12 (7, 20) C = 10 (6, 17) Non survivors T = 5 (2, 12) C = 5 (2, 12) ICU stay: Survivors T = 6 (3, 11) C = 4 (2, 8) Non survivors T = 4 (2, 9) C = 3 (1, 8) IMV T = 2625/3574 (73.4) C = 201,229/335,023 (60.1) NIMV T = 1175/3574 (32.9) C = 104,970/335,023 (31.3) Vasopressor use, Survivors T = 2 (1, 4) C = 2 (1, 3) Non-survivors T = 3 (2, 6) C = 2 (1, 4) Hospital mortality T = 1459/3574 (40.8) C = 92,060/335,023 (27.5) |
| Wang et al., 2020 [64] | N = 70 T = 33 C = 37 Age (years) T = 59.15 ± 8.11 C = 55.00 ± 9.92 M/F T = 13 (39.39)/20 (60.61) C = 14 (37.84)/23 (62.16) | Intravenous vitamin C 1 g (diluted to 10 mL) with a total of 3 g, 10 min after induction of anesthesia, 10 min before cardiac reanimation and at the moment of sternal closure. | Intravenous 10 mL saline. | ICU stay (h) T = 39.5 (20.8–44.3) C = 39.5 (20.5–44.5) LOHS (days) T = 14 (10–15) C = 12 (11–17) Atrial fibrillation T = 10/33 (30.30) C = 10/37 (27.03) Extubation time (min) T = 660 (401–920) C = 660 (358–862) Pulmonary complication T = 4 (12.12) C = 12 (32.43) |
| Wani et al., 2020 [48] | N = 100 T = 50 C = 50 Age (Median, IQR) T = 65 (59, 25–72) C = 70 (56, 25–72) Male: n (%) T = 28 (56%) C = 31 (62%) APACHE II Median (IQR) T = 18.5 (15–24.75) C = 20 (15–24) SOFA Mean ± SD (Range) T = 9.22 ± 3.54 (4–16) C = 9.36 ± 3.66 (2–16) Renal disease n (%) T = 6 (12.0%) C = 4 (8.0%) Acute kidney injury n (%) T = 37 (74%) C = 39 (78%) | Intravenous vitamin C (1.5 g q 6 hourly for 4 days or until discharge from the hospital), hydrocortisone (50 mg q 6 hourly for 7 days or until ICU discharge followed by a taper over 3 days) and intravenous thiamine (200 mg q 12 hourly for 4 days or until discharge from the hospital). | Standard of care, consisted of broad-spectrum antibiotics, intravenous fluids, vasopressors and mechanical ventilation as indicated. | Hospital mortality N (%) T = 12/50 (24%) C = 14/50 (28%) Ventilation N (%) T = 3/50 (6%) C = 3/50 (6%) Duration of vasopressor use (Mean ± SD, hours) Range T = 75.72 ± 30.29 (20–140) C = 96.13 ± 40.50 (30–200) LOHS (Mean ± SD, days) (Range) T = 11.82 ± 7.36 (4–36) C = 10.70 ± 6.39 (2–27) 30 day mortality N (%) T = 20/50 (40%) C = 21/50 (42%) SOFA score Day 4 T = 5.64 ± 3.55 C = 6.62 ± 3.94 |
| Yanase et al., 2020 [65] | N = 50 T = 25 C = 25 Age, years, (IQR) T = 67.0 (82.0, 74.0) C = 64.0 (59.0, 69.0) Sex, male T = 15/25 (60.0%) C = 23/25 (92.0%) Serum creatinine (μmol/L): T = 85.0 (75.0, 98.0) C = 92.0 (80.0, 100.0) | Vitamin C 1500 mg in normal saline (100-milliliter bag) administered 6 hourly in the vitamin C group. | Normal saline (100-milliliter bag) administered 6 hourly in the placebo group. | ICU LOS, days T = 1.4 (0.5, 2.5) C = 1.5 (0.5, 3.3) LOHS, days T = 13.2 (7.9, 20.2) C = 12.5 (8.1, 16.7) ICU mortality T = 1/25 (4.0%) C = 0/25 (0.0%) Hospital mortality T = 1/25 (4.0%) C = 0/25 (0.0%) AKI (1, 2, 3): T = 14/25; C = 12/25 Stage 1 T = 3/25 (12.0%) C = 1/25 (4.0%) Stage 2 T = 10/25 (40.0%) C = 9/25 (36.0%) Stage 3 T = 1/25 (4.0%) C = 2/25 (8.0%) Atrial fibrillation T = 11/25(44.0%) C = 8/25(32.0%) |
| Yoo et al., 2020 [39] | N = 79 T = 33 C = 46 Age, yr T = 66 (55.5–81) C = 73.5 (63–79) Male sex T = 20 (60.6) C = 34 (73.9 CKD T = 4 (12.1) C = 3 (6.5) APACHE II T = 26 (20.5–32.5) C = 30 (24–33.3) SOFA T = 13 (11–15) C = 12 (10–14.3) AKI T = 18 (54.5) C = 29 (63) RRT T = 7 (21.2) C = 13 (28.3) | The total supplementation of vitamin B1 was 200 mg/day intravenously infused 50 mg every 6 h. A total of 2 g of vitamin C intravenously infused 500 mg every 6 h. | No vitamin B and C supplementation, only standard of care. | 14-Day mortality T = 15/33 (45.5) C = 22/46 (47.8) 30-Day mortality T = 18/33 (54.5) C = 32/46 (69.6) ICU mortality T = 18/33 (54.5) C = 32/46 (69.6) In hospital mortality T = 19/33 (59.4) C = 33/36 (71.7) Ventilator free days T = 7.7 ± 10.8 C = 2.7 ± 7.3 ICU-free days T = 6.9 ± 9.8 C = 2.2 ± 6.5 |
| Zabet et al., 2016 [6] | N = 28 T = 14 C = 14 Age years, SD T = 64.14 ± 15.98 C = 63.71 ± 13.84 Sex (male) T = 10 (71.42) C = 11 (78.57) APACHE II score T = 19.07 ± 5.18 C = 23 ± 5.61 SOFA score T = 11.78 ± 2.22 C = 12.35 ± 3.00 |
25 mg/kg intravenous ascorbic acid every 6 h for 72 h. | 50 mL of dextrose 5% solution as intravenous infusion over 30 min. | ICU LOS (days) T = 21.45 ± 10.23 C = 20.57 ± 13.04 28-day mortality T = 2/14 (14.28) C = 9/14 (64.28) Duration of norepinephrine administration (h) T = 49.64 ± 25.67 C = 71.57 ± 1.60 |
| Ferron Celma et al., 2009 [47] | N = 20 T = 10 C = 10 Age (y) T = 67.8 ± 4.5 C = 65.1 ± 3.6 POSSUM Score T = 55.0 ± 3.3 C = 50.4 ± 1.4 Sex (Men/Women) T = 5/5 C = 6/4 Pressors T = 3/10 C = 2/10 Ventilatory support T = 3/10 C = 2/10 Creatinine (mg/dL) T = 2.15 ± 0.12 C = 1.99 ± 0.21 Lactate (meq/L) T = 3.22 ± 1.25 C = 1.97 ± 0.55 |
450 mg/day of the vitamin C administered in 5% dextrose water in 3 divided doses. | Identical administration of 5% dextrose. | Mortality T = 6/10 C = 4/10 |
| Habib et al., 2017 [66] | N = 100 T = 50 C = 50 Male T = 28 (56) C = 30 (60) Age Mean ± SD. T = 42.78 ± 9.49 C = 41.70 ± 10.2 APACHE II T = 22.0 ± 6.70 C = 21.8 ± 7.07 SOFA Mean ± SD. T = 10.2 ± 3.42 C = 11.4 ± 5.08 BUN mg/dL T = 100.23 ± 11.31 C = 100.40 ± 17.30 S. Cr mg/dL T = 3.22 ± 2.21 C = 5.83 ± 0.16 | Intravenous 1.5 gm vitamin C (ascorbic acid, Cevarol) every 6 h in the first 24 h after admission until ICU discharge plus conventional sepsis treatment. | Conventional sepsis treatment only. | Vasopressor Mean ± SD. T = 2.30 ± 1.2 C = 6.50 ± 2.57 Ventilator Mean ± SD. T = 4.60 ± 2.08 C = 7.87 ± 3.01 ICU LOS Mean ± SD. T = 10.00 ± 5.50 C = 14.10 ± 6.47 RRT T = 15/50 (30%) C = 13/50 (26%) Survivors T = 38/50 (76%) C = 32/50 (64%) Non-survivors T = 12/50 (24%) C = 18/50 (36%) |
| Tanaka et al., 2000 [67] | N = 37 T = 19 C = 18 Age, mean ±SD, y T = 40 ± 20 C = 49 ± 22 Male T = 13 C = 12 Inhalational injuries T = 15/19 C = 12/18 | An injectable ascorbic acid solution was diluted 10-fold with distilled water. The ascorbic acid solution was administered as a continuous intravenous infusion. | Fluid resuscitation without ascorbic acid. | LOHS, mean ± SD, d T = 40 ± 28 C= 49 ± 44 Ventilation, mean ± SD, d T = 12.1 ± 8.8 C = 21.3 ± 15.6 Mortality, no of patients T = 9/19 C = 7/18 |
| Galley et al., 1997 [68] | N = 30 T = 16 C = 14 Age median (range) T = 67 (21–78) C = 70 (22–89) Male: Female T = 13:3 C = 9:5 APACHE II median (range) T = 27.5 (17–54) C = 24 (11–35) | Intravenous antioxidant therapy comprising n-acetylcysteine 150 mg/kg for 30 min then 20 mg/kg/h plus bolus doses of 1 g ascorbic acid (vitamin C) and 400 mg alpha-tocopherol (vitamin E). | Comparable volume of 5% dextrose as placebo. | Mortality, n T = 11/16 C = 8/14 |
| Razmkon et al., 2011 [69] | N = 76 T1 = 26 T2 = 23 C = 27 Age (y; mean, range) T1 = 31.1 (16–67) T2 = 29.5 (19–75) C = 29.4 (16–68) Sex (male/female) T1 = 20/6 T2 = 20/3 C = 23/4 Admission GCSs (mean, range) T1 = 5.9 (3–8) T2 = 6.1 (3–8) C = 6.5 (3–8) | T1 group, low-dose vitamin C (500 mg/d IV) for 7 days; T2 group, high-dose vitamin C (10 g IV on the first (admission) day and repeated on the fourth day, followed by vitamin C 4 g/d IV for the remaining 3 days | Identical placebo. | Hospital mortality T1 = 7/26 T2 = 7/23 C = 8/27 Mortality after 2 months T1 = 8/26 T2 = 7/23 C = 8/27 Mortality after 6 months T1 = 9/26 T2 = 7/23 C = 8/27 |
| Bansal et al., 2011 [70] | N = 39 [T = 19, C = 20] Age (years) Mean ±SD T = 39.9 (10.9) C = 38.6 (11.4) Males (%) T = 15 (79) C = 15 (75) APACHE score (SD) T = 11.2(2.9) C = 11.5 (2.7) | vitamin C (1000 mg in 100 mL of normal saline), vitamin E (200 mg oral) and vitamin A (10,000 IU intramuscularly). | The control group was given the standard treatment only. | Organ dysfunction(day 7) T = 7 /19 (37) C = 8/20 (40) LOHS (days) Mean (SD) T = 12.8 (3.9) C = 15.1 (5.43) Renal insufficiency T = 4/19 C = 4/20 Mortality T = 0/19 C= 2/20 |
| Sevransky et al., 2021 [46] | N = 501(T = 252, C = 249) Median age, 62 [IQR, 50–70] years Female: 46% |
Intravenous vitamin C (1.5 g), thiamine (100 mg) and hydrocortisone (50 mg) every 6 h. | Matching placebo. | Mortality in 30-day: T:56 /252; C: 60/249 Mortality 180-day: T:102 /252; C: 94/249 ICU mortality: T:52 /252; C: 49/249 ICU stay, median (IQR), day; T:4 (2–8) [n = 250] C:4 (2–8) [n = 245] Hospital stay, median (IQR), day; T: 10 (6–17) [n = 250]; C: 9 (5–17) [n = 246] Ventilator- and vasopressor-free days {median(IQR)}: T: 25 (0–29) days; C: 26 (0–28) days |