Table 1 Baseline Characteristics of All Patients
Variable
|
All Patients(n=54)
|
Vitamin C(n=26)
|
Placebo(n=28)
|
P Value
|
Demographics
|
|
Age, years
|
67.4±12.4
|
67.1±10.6
|
67.7±14.0
|
0.86
|
|
Gender, male, n, %
|
36(66.7)
|
14(53.8)
|
22(78.6)
|
0.08
|
|
Height, cm
|
168.8±6.6
|
167.0±6.9
|
170.8±5.8
|
0.08
|
|
Weight, kg
|
62.0±10.5
|
59.7±11.2
|
64.4±9.4
|
0.16
|
Centres
|
|
Zhongnan Hospital of Wuhan University, n, %
|
10(18.5)
|
5(19.2)
|
5(17.9)
|
-
|
|
Leishenshan (Thunder God Mountain) Hospital, n, %
|
38(70.4)
|
18(69.2)
|
20(71.4)
|
-
|
|
Taihe Hospital, n, %
|
6(11.1)
|
3(11.5)
|
3(10.7)
|
-
|
General condition on randomization day
|
|
Highest temperature, ℃
|
37±1.0
|
37.3±0.8
|
37.4±1.1
|
0.65
|
|
Highest Heart rate, times/min
|
93.2±18.4
|
96.6±18.6
|
90.2±18.1
|
0.21
|
|
Lowest MAP, mmHg
|
91.0(17.9)
|
88.4(16.6)
|
93.4(18.9)
|
0.31
|
|
Highest RR, times/min
|
25[20-36]
|
25[21-31]
|
24[20-30]
|
0.19
|
|
Lowest SPO2, %
|
93[88-98]
|
93[81-98]
|
93[90-97]
|
0.93
|
|
APACHE II score
|
13.5[10.3-15.8]
|
14.0[11.0-16.0]
|
13.0[9.5-15.0]
|
0.24
|
|
GCS score
|
15.0[14.5-15.0]
|
15.0[13.0-15.0]
|
15.0[15.0-15.0]
|
0.75
|
Comorbidities, n, %
|
|
Diabetes
|
16(29.6)
|
7(26.9)
|
9(32.1)
|
0.77
|
|
Hypertension
|
24(44.4)
|
10(38.5)
|
14(50.0)
|
0.42
|
|
Coronary heart disease
|
12(22.2)
|
4(15.40 )
|
8(28.6)
|
0.33
|
|
Chronic lung disease
|
3(5.6)
|
1(3.8)
|
2(7.1)
|
1.00
|
|
Chronic renal failure
|
1(1.85)
|
1(3.8)
|
0(0.0)
|
0.48
|
|
Malignant tumor
|
3(5.6)
|
3(11.5)
|
0(0.0)
|
0.11
|
|
Nervous system diseases
|
11(20.4)
|
7(26.9)
|
4(14.3)
|
0.32
|
Median duration of symptoms before HDIVC therapy, days
|
17.0[11.0-25.0]
|
22.0[11.0-33.0]
|
15.0[11.0-22.0]
|
0.18
|
Other treatments during 7-days HDIVC therapy
|
Corticosteroid use, n, %
|
18(33.3)
|
8(36.4)
|
109(38.5)
|
1.00
|
Antibiotic, n, %
|
51(94.4)
|
24(92.3)
|
27 (96.4)
|
1.00
|
Net fluid balance, mL/kg/24 h
|
|
Day 1
|
190[-1487-662]
|
252[-252-810]
|
155[-520-499]
|
0.39
|
|
Day 2
|
156[-349 -653]
|
192[-508-883]
|
121[-90 -577]
|
0.94
|
|
Day 3
|
62[-703-768]
|
-240[-1004 -233]
|
463[5-1351]
|
0.02
|
|
|
|
|
|
|
|
|
Data were expressed as mean ± standard deviation, as median [interquartile range], or as numbers (percentage). Comparisons were performed using Student’s t test, Wilcoxon–Man–Whitney, Chi square, or Fischer’s exact.
Abbreviations: SD, standard deviation; IQR, interquartile range; APACHE, Acute Physiology and Chronic Health Evaluation; GCS, Glasgow coma scale; HDIVC: high dose intravenous vitamin C.
Table 2 Outcomes in a Trial of HDIVC in patients with Covid-19.
Variable
|
Day
|
Vitamin C(n=26)
|
Placebo(n=28)
|
Difference, Coefficient (95% CI)
|
P Value
|
SOFA scores
|
1
|
3.5[3-6.8]
|
2.0[3.0-5.0]
|
0.7(-0.9 to 2.3)
|
0.37
|
3
|
4.0[2.0-8.0]
|
4.0[3.0-7.0]
|
-0.3(-2.6 to 1.9)
|
0.50
|
7
|
3.0[2.0-5.8]
|
6.0[2.50-8.0]
|
-1.14(-3.1 to 0.8)
|
0.24
|
Lowest P/F
|
1
|
188.7±95.4
|
210.6±128.5
|
34.6(-91.9 to 48.0)
|
0.53
|
3
|
217.3±96.5
|
189.5±101.9
|
30.7(-34.3 to 89.9)
|
0.37
|
7
|
228.5±72.6
|
150.7±75.3
|
22.1(33.2 to 122.5)
|
0.01
|
Advanced life support, n, %
|
|
CRRT
|
1
|
1(3.8)
|
3(10.7)
|
OR0.3(0.0 to 3.5)
|
0.61
|
|
7
|
3(12.5)
|
1(3.8)
|
OR3.57(0.4 to 36.9)
|
0.34
|
|
ECMO
|
1
|
1(3.8)
|
2(7.1)
|
OR0.5(0.0 to 6.0)
|
1.00
|
|
7
|
0(0.0)
|
2(9.1)
|
OR0.5(0.4 to 0.7)
|
0.50
|
|
Vasopressor use
|
1
|
9(36.0)
|
6(21.4)
|
OR2.1(0.6 to 6.9)
|
0.36
|
|
7
|
4(16.7)
|
4(17.4)
|
OR1.2(0.4 to 3.8)
|
1.00
|
|
Oxygen-support category
|
|
HFNC
|
1
|
7(26.9)
|
11(39.3)
|
OR0.6(0.2 to 1.8)
|
0.40
|
|
7
|
11(47.8)
|
9(39.1)
|
OR14.3(0.4 to 4.6)
|
0.77
|
|
NIV
|
1
|
7(26.9)
|
7(25.0)
|
OR1.1(0.3 to 3.7)
|
1.00
|
|
7
|
7(30.4)
|
2(8.7)
|
OR4.6(0.8 to 25.2)
|
0.14
|
|
IMV
|
1
|
10(38.5)
|
11(39.3)
|
OR1.0(0.3 to 2.9)
|
1.00
|
|
7
|
10(43.5)
|
11(47.8)
|
OR0.8(0.3 to 2.7)
|
1.00
|
Complications, n, %
|
|
Septic shock
|
9(34.6)
|
8(28.6)
|
OR1.3(0.4 to 2.4)
|
0.77
|
|
Acute cardiac injury
|
7(26.9)
|
13(48.1)
|
OR0.4(0.1 to 1.3)
|
0.16
|
|
Acute liver injury
|
12(48.0)
|
13(48.1)
|
OR1.0(0.3 to 3.0)
|
1.00
|
|
Acute kidney injury
|
3(12.0)
|
6(22.2)
|
OR0.5(0.1 to 2.2)
|
0.50
|
|
Coagulation disorders
|
9(34.6)
|
7(25.9)
|
OR1.5(0.5 to 5.0)
|
0.56
|
Outcomes
|
|
HFNC days to day 28, days
|
0.5[0.0 -8.3]
|
2.0[0.0 -7.0]
|
0.2(-2.9 to 3.3)
|
0.85
|
|
NIV days to day 28, days
|
0.0[0.0 -3.3]
|
0.0[0.0 -1.8]
|
1.2(-1.2 to 3.7)
|
0.68
|
|
IMV days to day 28, days
|
1.5[0.0 -19.0]
|
6.0[0.0-16.0]
|
-0.8(-6.4 to 4.9)
|
0.60
|
|
IMV- free days to day 28, days c
|
26.5[1.5-28.0]
|
10.5[0.0 -28.0]
|
4.8(-2.3 to 11.9)
|
0.56
|
|
Patients’ condition deterioration, n, % d
|
3(11.5)
|
6(24.0)
|
0.4(0.1 to 1.7)
|
0.19
|
|
Patients’ condition improvement, n, % e
|
5(19.2)
|
6(21.4)
|
0.9(0.2 to 3.3)
|
0.84
|
|
ICU mortality, n, %
|
5(19.2)
|
10(35.7)
|
HR0.6(0.7 to 1.6)
|
0.23
|
|
ICU mortality of patients with SOFA ≥3, n, %
|
4(18.2)
|
10(50.0)
|
HR0.2(0.1 to 0.9)
|
0.03
|
|
ICU stay, days
|
23.6±14.6
|
18.4±13.2
|
5.2(-2.4 to 12.8)
|
0.17
|
|
Hospital mortality, n, %
|
5(19.2)
|
10(35.7)
|
HR0.6(0.7 to 1.6)
|
0.23
|
|
Hospital mortality of patients with SOFA ≥3, n, %
|
4(18.2)
|
10(50.0)
|
HR0.2(0.1 to 0.9)
|
0.03
|
|
Hospital stay, days
|
36.3±16.2
|
33.8±16.4
|
2.4(-7.1 to 11.9)
|
0.61
|
|
28-day mortality, n, %
|
5(19.2)
|
9(32.1)
|
HR0.5(0.1 to 1.8)
|
0.36
|
|
28-days mortality of patients with SOFA ≥3, n, %
|
4(18.2)
|
9(45.0)
|
HR0.3(0.1 to 1.1)
|
0.06
|
Data were expressed as mean ± standard deviation, as median [interquartile range], or as numbers (percentage). Hazard ratio and 95% CI were estimated by Cox proportional risk model. Odd ratio with 95% CI were calculated by binary logistic regression for the rest. Absolute diference was expressed as a percentage with the 95% CI range. P values were calculated by logistic regression.
a Acute cardiac injury was defined as the serum levels of troponin I were above the 99th percentile upper reference limit or new abnormalities were shown in electrocardiography and echocardiography.
b Acute kidney injury was identified according to the Kidney Disease: Improving Global Outcomes definition.
c IMV-free days were defined as the number of days a patient was extubated from mechanical ventilation, after ICU admission to day 28. Days requiring reintubation were subtracted. If the patient died in the hospital post extubation, a value of zero was assigned.
d Patients’ condition deterioration was defined that the patient required HFNC or NIV on day 1, and transferred to ECMO, or IMV, or dead on day 7.
e Patients’ condition improvement was defined that the patient required ECMO or IMV on day 1 and transferred to HFNC, or NIV, or discharged from ICU on day 7.
Abbreviations: HDIVC: high dose intravenous vitamin C; COVID-19, coronavirus disease 2019; SD, standard deviation; IQR, interquartile range; HR, hazard ratio; OR, odd ratio; CI, confidence interval; SOFA: sequential organ failure assessment; P/F, PaO2/FiO2; CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation; HFNC, high flow nasal cannula; IV, invasive ventilation; IMV, invasive mechanical ventilation; NIV, noninvasive mechanical ventilation; ICU, intensive care unit.
Table 3 Laboratory findings in a Trial of HDIVC in patients with Covid-19.
Variable
|
Day
|
Vitamin C(n=26)
|
Placebo(n=28)
|
Difference, Coefficient (95% CI)
|
P Value
|
Leukocyte count, 10^9
|
1
|
9.50±5.04
|
11.45±7.22
|
-1.95(-5.38 to -1.47)
|
0.26
|
3
|
8.59[5.74-11.48]
|
8.44[7.09-12.23]
|
-0.40(-3.50 to 2.70)
|
0.67
|
7
|
10.23±6.73
|
9.64±5.41
|
0.59(-2.96 to 4.14)
|
0.74
|
Neutrophil count, 10^9
|
1
|
8.21±4.81
|
10.19±7.08
|
-1.98(-5.31 to 1.35)
|
0.24
|
3
|
6.19[4.52-10.45]
|
7.07[5.68-9.94]
|
-0.51(-3.48 to 2.47)
|
0.50
|
7
|
8.05±6.47
|
8.15±5.45
|
-0.11(-3.58 to 3.37)
|
0.95
|
Neutrophil ratio, %
|
1
|
83.50±9.63
|
85.83±9.92
|
-2.33(-7.74 to -3.07)
|
0.39
|
3
|
85.65[77.05-91.42]
|
83.30[75.53-91.78]
|
4.03(-6.32 to 14.38)
|
0.70
|
7
|
78.45±15.76
|
81.66±11.45
|
-3.21(-11.22 to 4.79)
|
0.42
|
IL-6
|
1
|
22.56[8.87-85.54]
|
54.73[12.34-145.47]
|
-6.21(-129.71 to 117.29)
|
0.61
|
3
|
113.10[21.80-288.73]
|
37.24[5.59-85.28]
|
92.44(-25.13 to 210.01)
|
0.07
|
7
|
19.42[10.59-29.16]
|
158.00[15.29-259.60]
|
-165.76(-301.72 to -29.79)
|
0.04
|
Lymphocyte count, 10^9
|
1
|
0.55[0.36-0.99]
|
0.53[0.37-0.95]
|
0.09(-0.17 to 0.36)
|
0.49
|
3
|
0.56[0.33-0.95]
|
0.71[0.47-1.05]
|
-2.61(-8.59 to 3.37)
|
0.50
|
7
|
0.81[0.43-1.05]
|
0.65[0.42-0.97]
|
1.11(-0.76 to 2.98)
|
0.25
|
Lymphocyte ratio, %
|
1
|
9.68±6.97
|
8.12±7.33
|
1.62(-2.32 to 5.57)
|
0.41
|
3
|
10.08±9.22
|
8.71±4.90
|
1.37(-2.67 to 5.40)
|
0.88
|
7
|
13.14±11.31
|
6.83[5.05 -13.42]
|
3.34(-2.13 to 8.81)
|
0.23
|
PCT, ng/mL
|
1
|
0.16[0.08-0.6]
|
0.19[0.05-0.53]
|
-9.94(-29.28 to 9.41)
|
0.80
|
3
|
0.35[0.09-3.22]
|
0.31[0.08-1.11]
|
-6.59(-20.46 to 7.28)
|
0.84
|
7
|
0.26[0.13-14.79]
|
0.20[0.07-0.74]
|
13.28(-17.91 to 44.48)
|
0.18
|
CRP, mg/L
|
1
|
39.86[3.91-86.85]
|
56.84[40.19-100.20]
|
-23.16(-69.46 to 23.14)
|
0.19
|
3
|
43.52[3.41- 65.72]
|
66.34[29.76-107.39]
|
-4.78(-68.08 to 58.53)
|
0.28
|
7
|
29.47[10.95-110.93]
|
30.20[2.3-131.70]
|
-12.60(-75.34, 50.14)
|
0.68
|
Total bilirubin, umol/L
|
1
|
8.55[6.78- 15.60]
|
10.80[7.40-18.30]
|
-1.45(-7.30 to 4.41)
|
0.28
|
3
|
8.40[6.70-16.10]
|
14.85[9.85-25.48]
|
-9.46(-18.33 to -0.59)
|
0.03
|
7
|
8.30[6.53-16.15]
|
15.30[9.03-27.68]
|
-4.19(-15.88 to 7.50)
|
0.11
|
, umol/L
|
1
|
64.20[46.58-85.45]
|
64.20[52.00 -81.70]
|
26.35(-50.86 to 103.56)
|
0.57
|
3
|
60.30[37.65-80.38]
|
70.35[49.80-100.88]
|
2.52(-39.89 to -44.93)
|
0.15
|
7
|
57.50[39.95-71 ]
|
63.50[51.70-104.50]
|
-12.43(-45.59 to 20.73)
|
0.13
|
BUN, mmol/L
|
1
|
7.11[4.48-11.10]
|
6.50[4.90-9.94]
|
9.34(-8.75 to 27.44)
|
0.84
|
3
|
7.58±5.01
|
8.56[5.13-11.39]
|
-2.10(-5.22 to -1.02)
|
0.11
|
7
|
8.48±5.69
|
7.80[5.10-10.50]
|
-0.73(-4.12 to 2.66)
|
0.48
|
PT, s
|
1
|
13.25[12.35-14.63]
|
12.90[12.50-13.80]
|
-0.58(-2.35 to 1.19)
|
0.97
|
3
|
13.90±3.24
|
13.25[12.70-15.05]
|
-0.29(-1.97 to 1.39)
|
0.33
|
7
|
12.99±2.55
|
13.05[12.35-14.60]
|
-0.27(-1.67 to 1.14)
|
0.08
|
Data were expressed as mean ± standard deviation, as median [interquartile range]. Odd ratio with 95% CI were calculated by binary logistic regression for the rest. P values were calculated by logistic regression.
Abbreviations: SD, standard deviation; IQR, interquartile range; HR, hazard ratio; OR, odd ratio; CI, confidence interval; HDIVC: high dose intravenous vitamin C; COVID-19, coronavirus disease 2019; SD, standard deviation; IQR, interquartile range; PCT, procalcitonin; CRP, C-reactive protein; BUN, blood urea nitrogen; PT, prothrombin time,IL-6, interleukin-6.