Infectious Diseases

ISSN: 2374-4235 (Print) 2374-4243 (Online) Journal homepage: https://www.tandfonline.com/loi/infd20

Combination of vitamin C, thiamine and

hydrocortisone added to standard treatment in
the management of sepsis: results from an open
label randomised controlled clinical trial and a
review of the literature

Saleem Javaid Wani, Showkat A Mufti, Rafi A. Jan, SU Shah, Syed Mudassir
Qadri, Umar Hafiz Khan, Farhana Bagdadi, Nazia Mehfooz & Parvaiz A. Koul

To cite this article: Saleem Javaid Wani, Showkat A Mufti, Rafi A. Jan, SU Shah, Syed Mudassir
Qadri, Umar Hafiz Khan, Farhana Bagdadi, Nazia Mehfooz & Parvaiz A. Koul (2020): Combination
of vitamin C, thiamine and hydrocortisone added to standard treatment in the management of
sepsis: results from an open label randomised controlled clinical trial and a review of the literature,
Infectious Diseases, DOI: 10.1080/23744235.2020.1718200

To link to this article: https://doi.org/10.1080/23744235.2020.1718200

Published online: 28 Jan 2020.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=infd20
INFECTIOUS DISEASES, https://doi.org/10.1080/23744235.2020.1718200
2020; VOL. 0,
NO. 0, 1–8

ORIGINAL ARTICLE

Combination of vitamin C, thiamine and

hydrocortisone added to standard treatment in the
management of sepsis: results from an open label
randomised controlled clinical trial and a review of
the literature

Saleem Javaid Wania, Showkat A Muftib, Rafi A. Jana, SU Shaha, Syed Mudassir Qadria, Umar Hafiz Khana,
Farhana Bagdadia, Nazia Mehfooza and Parvaiz A. Koula
a
Department of Internal and Pulmonary Medicine, Sheri Kashmir Institute of Medical Sciences, Srinagar, India; bDepartment of
Emergency Medicine, Sheri Kashmir Institute of Medical Sciences, Srinagar, India

ABSTRACT
Background: Combination of vitamin C, hydrocortisone and thiamine have recently been used in sepsis but data of effi-
cacy are conflicting and no data are available from developing countries. We sought to study the effect of addition of this
combination to standard care in patients with sepsis/septic shock in a north Indian setting.

Methods: In a prospective, open label, randomised fashion, 100 patients with sepsis/septic shock were recruited to receive
either standard therapy alone (control group, n ¼ 50) or a combination of vitamin C, thiamine and hydrocortisone (treat-
ment group, n ¼ 50) in addition. The patients were followed for various clinical and laboratory parameters, in-hospital and
30-day mortality, duration of vasopressor use, lactate clearance, duration of hospital stay, and change in serum lactate and
the SOFA score over the first 4 days.

Results: The 2 groups were matched for basic characteristics. The in-hospital mortality (28% in controls and 24% in treat-
ment group, p ¼ .82) and 30-day mortality (42% in controls and 40% in treatment group, p ¼ 1.00) was not significantly dif-
ferent in the 2 groups. However, there was a significant difference in duration of vasopressor use (96.13 ± 40.50 h in control
group v/s 75.72 ± 30.29 h in treatment group, p value ¼ .010) and lactate clearance (control group: 41.81% v/s treatment
group: 56.83%, p value ¼.031) between 2 groups.

Conclusions: Addition of vitamin C, hydrocortisone, and thiamine into standard care of sepsis does not improve in-hospital
or 30 day mortality. However lower vasopressor use and faster lactate clearance is observed with treatment.

KEYWORDS ARTICLE HISTORY CONTACT

Sepsis Received 1 November 2019 Parvaiz A. Koul
shock Revised 10 January 2020 parvaizk@gmail.com
thiamine Accepted 13 January 2020 Department of Internal and Pulmonary
vitamin C Medicine, Sheri Kashmir Institute of Medical
steroids Sciences, Srinagar 190011, J&K, India

ß 2020 Society for Scandinavian Journal of Infectious Diseases

2 S. J. WANI ET AL.
Introduction
Sepsis is a clinical syndrome that complicates severe
infection and is characterised by systemic inflammation
and widespread tissue injury and organ dysfunction. The
clinical process usually begins with infection, which
potentially leads to sepsis and organ dysfunction [1].
Sepsis has a huge global burden with around 15–19 mil-
lion cases per year; majority of the cases occurring in
low income countries [2]. Sepsis is associated with a
high mortality rate from 10 to 52 percent [3–7].
Mortality rates increase with the severity of sepsis rang-
ing from 7% in systemic inflammatory response syn-
drome (SIRS) to about 46% in septic shock [8,9]. The
mortality is particularly high in low income countries
including India, having been reported to be >60%
[10–12]. In a recent Indian study, in-hospital mortality
and 28-day mortality of severe sepsis were 65.2% and
64.6%, respectively [12]. Despite aggressive antimicrobial
therapy along with haemodynamic, metabolic and circu-
latory support, prognosis and survival continues to be
poor and novel therapies are being tried with conflict-
ing results.
Recently Marik et al. [13], conducted a retrospective
study where they studied the role of combination of
Vitamin C, Hydrocortisone and Thiamine for the treat-
ment of severe sepsis and septic shock and found that
the combination was effective in preventing progressive
organ dysfunction and reducing mortality of the
patients. Subsequent studies included an randomised
controlled trial (RCT) by Balakrishnan et al. in post-surgi-
cal patients having undergone cardiac surgery [14], and
few retrospective studies [15–19] which showed conflict-
ing results. However, there is no well defined RCT that
has assessed the effect of combination of vitamin C,
hydrocortisone and thiamine for the treatment of sepsis
and septic shock, especially in Indian patients. We con-
ducted this study against this backdrop to assess the
effect of combination of Vitamin C, Hydrocortisone and
Thiamine for the treatment of Sepsis and Septic shock in
resource limited settings (Figure 1).
Methods
The study was a single centre, prospective, open label,
randomised controlled trial conducted in the depart-
ment of Internal Medicine and Emergency Medicine at
SKIMS, Srinagar, a 850 - bedded tertiary care cum refer-
ral centre located in the northern Indian state of Jammu
and Kashmir from April 2018–June 2019.
120
Duraon of Vasopressors(Hours)
100 96.13
80 75.72
H
o
u 60
r
s 40
20
0
Control Treatment
Figure 1. Duration of vasopressor use. p value ¼ .01.
Patients who were admitted with a diagnosis of sep-
sis and septic shock with a serum lactate level of
>2 mmol/l were enrolled in the study. The diagnosis of
sepsis and septic shock was based on The Third
International Consensus Definitions for Sepsis and Septic
Shock [9], wherein sepsis is defined as a life-threatening
organ dysfunction caused by a dysregulated host
response to infection. Organ dysfunction is represented
by an increase in the Sequential [sepsis-related] Organ
Failure Assessment (SOFA score of 2 points or more; and
septic shock is a subset of sepsis who fulfill the criteria
for sepsis and, despite adequate fluid resuscitation,
require vasopressors to maintain a mean arterial pres-
sure (MAP) 65 mmHg and have a lactate >2 mmol/L
(>18 mg/dL) [9]. Patients were mostly enrolled from the
emergency department. Sequential patients who con-
sented to participate in the study were included.
Patients aged less than <18 years and pregnant patients
were excluded from the study. Patients were enrolled
randomly into treatment and control groups by a com-
puter generated randomisation. A total of 100 patients
were enrolled in the study, 50 in each group.
Baseline and demographic data including age, sex,
admitting diagnosis, co-morbidities, requirement for
mechanical ventilation, use and duration of vasopres-
sors, daily urine output (for first 4 days), and laboratory
data was obtained from all patients and recorded on a
predefined proforma. Patients were considered immuno-
compromised if they would be taking more than 10 mg
of prednisone equivalent per day for at least 2 weeks,
receiving cytotoxic therapy or diagnosed with the
acquired immunodeficiency syndrome. Complete blood
count, serum urea, creatinine, total bilirubin and lactate
levels was recorded daily for the first 4 days. Acute kid-
ney injury (AKI) was diagnosed as per the Kidney
Disease Improving Global Outcomes (KDIGO) criteria as
an increase of the serum creatinine >0.3 mg/dl or a level
>1.5 times the baseline value [20]. If the baseline serum
creatinine was not known, a value >1.5 mg/dl was
 INFECTIOUS DISEASES 3

considered as diagnostic of AKI. The patient’s admission Results

APACHE II and APACHE IV score was recorded. SOFA
Table 1 shows the baseline characteristics of the patients
(Sepsis Related Organ Failure Assessment) score was cal-
of the two groups. As can be observed, the baseline
culated daily for first 4 days.
characteristics did not differ significantly among the 2
The overall management (standard care) of patients
groups. Majority of the patients fcontrol group 36(72%)
with sepsis and septic shock in both the treatment and
v/s 34(68%) treatment groupg had respiratory tract
the control groups was similar and consisted of broad
infection as the source of sepsis as shown in Table 1.
spectrum antibiotics, intravenous fluids, vasopressors
Table 2 depicts the various outcomes in the 2 groups.
and mechanical ventilation as indicated. Antibiotics were
Fourteen (28%) patients in the control group and
modified according to the culture and sensitivity reports.
12(24%) in treatment group (p value ¼ .82), died during
Patients in the treatment group, in addition received
the course of hospitalisation whereas 30-day mortality
intravenous vitamin C (1.5 grams q 6 hourly for 4 days
was 42% (n ¼ 21) in the control group and 40% in the
or until discharge from the hospital), hydrocortisone
treatment group (n ¼ 20, p ¼ 1.0). However, the mean
(50 mg q 6 hourly for 7 days or until ICU discharge fol-
duration of vasopressor use was significantly higher in
lowed by a taper over 3 days) and intravenous thiamine
the control group compared to the treatment group
(200 mg q 12 hourly for 4 days or until discharge from
(control group 96.13 ± 40.50 h v/s 75.72 ± 30.29 h treat-
the hospital). Vitamin C was administered as an infusion
ment group, p value ¼ .01) (Figure 1). Also, there was a
over 30 to 60 min in a 100 ml solution of either dextrose
significant difference in lactate clearance between the
5% in water or 0.9% saline. Intravenous thiamine was
two groups (control group: 41.81% v/s treatment group:
given in 50 ml of either dextrose 5% in water or normal
56.83%, p value ¼ .03). No significant difference in
saline and administered as a 30 min infusion. Triple ther-
change of SOFA score was seen between the two
apy was administered within few hours (in all cases in
<24 h) of admission.
The primary objective of our study was in-hospital Table 1. Baseline characteristics of the participants.
mortality between the treatment and control groups. Control group Treatment group
Baseline characteristics (n ¼ 50) (n ¼ 50) p Value
Secondary objectives included 30-day mortality, duration
Age in years (Median & IQR) 70 (56, 25–72) 65 (59, 25–72) .84
of hospital stay, duration of vasopressor therapy, lactate Male: n (%) 31 (62%) 28 (56%) .68
clearance, change in serum lactate and the SOFA score Female: n (%) 19 (38%) 22 (44%)
Severity of illness
over the first 4 days. Lactate clearance was calculated APACHE II 20 (15–24) 18.5 (15–24.75) .94
Median (IQR)
according to the following formula: APACHE IV 79.5 (62–89.75) 73 (60.25–81.5) .29
Median (IQR)
(Serum lactate level on day 1 – Serum lactate level on SOFA score 9.36 ± 3.66 (2–16) 9.22 ± 3.54 (4–16) .82
Mean ± SD (Range)
day 3/Serum lactate level on day 1  100) Comorbidities
Hypertension n (%) 25 (50.0%) 34 (68.0%) .10
COPD n (%) 14 (28.0%) 15 (30.0%) 1.00
Ethics clearance Cardiac disease n (%)
d
13 (26.0%) 8 (16.0%) .32
Diabetes mellitus n (%) 9 (18.0%) 11 (22.0%) .80
Malignancy n (%) 8 (16.0%) 4 (8.0%) .35
The study was approved by institutional ethical commit- Immunocompromiseda n (%) 8 (16.0%) 3 (6.0%) .20
tee of SKIMS (IEC/SKIMS Protocol # RP: 42/2018) and Renal disease n (%)
b
4 (8.0%) 6 (12.0%) .74
Hepatic diseasec n (%) 4 (8.0%) 0 (0.0%) .11
was registered in the Clinical Trials Registry of India Heart failure n (%) 1 (2.0%) 1 (2.0%) 1.00
(CTRI/2018/08/015193). Acute kidney injury n (%) 39 (78%) 37 (74%) .81
Admission diagnosis
Sepsis n (%) 12 (24%) 4 (8%) .054
Septic Shock n (%) 38 (76%) 46 (92%)
Statistical analysis Primary Diagnosis
Pneumonia n (%) 36 (72%) 34 (68%) .70
The data was analysed using parametric and non- Urosepsis n (%) 11 (22%) 12 (24%)
Biliary (Cholangitis) n (%) 2 (4%) 2 (4%)
parametric tests using Statistical Package for Social Acute Gastroenteritis n (%) 1 (2%) 1 (2%)
Scientists (SPSS) ver 22.0 (IBM, USA). The statistical tech- Meningoencephalitis n (%) 0 (0%) 1 (2%)
a
niques used to analyse the data included two sample Patients were considered immunocompromised if they would be taking more
than 10 mg of prednisone equivalent per day for at least 2 weeks, receiving
independent t-test, Mann Whitney U test, Chi square cytotoxic therapy or diagnosed with the acquired immunodeficiency syndrome.
b
test, Fishers Exact test and Logistic regression. Values Renal disease: Chronic Kidney Disease.
c
Hepatic disease: Chronic Liver Disease, Extrahepatic biliary obstruction.
have been expressed as mean ± SD and a p value <.05 d
Cardiac disease: Coronary artery disease, Atrial fibrillation, heart block, rheum-
atic heart disease, cardiomyopathy.
was considered significant.
4 S. J. WANI ET AL.
Table 2. Depicting outcomes in the treatment and the control group.
Variables
In hospital mortality N (%)
Requirement of mechanical ventilation N (%)
Duration of vasopressor use (Mean ± SD, hours)fRangeg
Duration of hospital stay (Mean ± SD, days)fRangeg
30 day mortality N (%)
Lactate clearance (%)
SOFA score Day 4
groups from day 1 to day 4. Day 4 SOFA score (control
6.62 ± 3.94 vs 5.64 ± 3.55 in treatment group, p value ¼
.2). Invasive mechanical ventilation was required in 6%
(n ¼ 3) patients in each group. And the mean hospital
stay was not significantly different in the 2 groups (con-
trol group 10.70 ± 6.39 days v/s 11.82 ± 7.36 days in treat-
ment group, p value ¼ .42). On multivariate analysis, only
duration of vasopressor use had a significant correlation
with in hospital mortality (p value ¼ .02).
Discussion
Our study showed that addition of vitamin C, hydrocorti-
sone and thiamine to standard medical care in patients
with sepsis and septic shock was not associated with
any improvement of in-hospital or 30-day mortality but
led to reduction of duration of vasopressor use and
increase in lactate clearance. Patients with sepsis have
been reported to carry an increased risk of death (up to
20 percent) as well as an increased risk of further sepsis
and recurrent hospital admissions (up to 10 percent
patients are readmitted), most deaths occurring within
the first six months but the risk staying elevated even at
two years [21–25]. In a recent Indian study, in-hospital
mortality and 28-day mortality of severe sepsis were
65.2% and 64.6%, respectively [12].
Data regarding use of the triple therapy in patients of
sepsis and septic shock is sparse and is only restricted
to few retrospective reviews and a single RCT [13–19].
Table 3 summarises the results of the previous studies
which are rather conflicting in their conclusions. While
in the retrospective review of 94 patients by Marik et al.
[13], use of triple therapy was associated with signifi-
cantly lower hospital mortality (40.4% in control vs 8.5%
in treatment group), in a larger subsequent study includ-
ing 1144 patients of septic shock [15], use of the com-
bination of vitamin C and thiamine did not result in a
significant reduction in-hospital and 28-day mortality.
However on subgroup analysis, among patients with
low albumin (<3.0 mg/dL) and SOFA score >10, treat-
ment was associated with lower in-hospital mortality.
Despite the large sample size the study had few
Control group (n ¼ 50) Treatment group (n ¼ 50) p Value
14 (28%) 12 (24%) .82
3 (6%) 3 (6%) 1.00
96.13 ± 40.50 f30–200g 75.72 ± 30.29 f20–140g .01
10.70 ± 6.39 f2–27g 11.82 ± 7.36 f4–36g .41
21 (42%) 20 (40%) 1.00
41.81 56.83 .03
6.62 ± 3.94 5.64 ± 3.55 .20
limitations. It was a retrospective study, the combination
therapy was limited in the early resuscitation period,
and the treatment duration was believed to have been
rather short to effect a change in the clinical outcome.
Further, all patients did not receive combin-
ation therapy.
In another more recent retrospective study by Kim
et al. [16] that included 99 patients with severe pneu-
monia (53 in treatment group and 46 in control group),
there was no significant difference in mortality in treat-
ment group (21%) when compared to the control group
(37%, p ¼ .07). However, in the propensity-matched
cohort (n ¼ 36/group), the treated patients had signifi-
cantly less hospital mortality than the control group
(17% vs. 39%; p ¼ .04). The treatment and control groups
did not differ significantly in terms of number of vaso-
pressor-free and ventilator-free days at day 28. The
study had several limitations. It was a single centre non-
randomised study and the use of non concurrent control
patients increase the risk of selection bias. There were
differences in various baseline characteristics and the
mortality difference became statistically significant only
in the propensity-matched cohort or in the subgroup of
patients with more severe pneumonia and 30 out of the
46 control group patients received corticosteroids.
In a subsequent retrospective observation cohort
study by Litwak et al. [17], that included 94 patients of
sepsis/septic shock (47 in standard care group and 47 in
triple therapy group), use of triple therapy (vitamin C,
steroids and thiamine) was not associated with better
patient outcome in terms of reduction in hospital mor-
tality (40.4% in standard care vs. 40.4% in triple therapy
group; p ¼ 1.00). The study was limited in that the triple
therapy regimen was not protocolized at the institution,
and 27 patients (57%) in the treatment group did not
receive triple therapy for the full treatment duration. Of
these patients, the most common reasons for insufficient
duration of therapy were therapy discontinuation by the
primary team or patient death. Confirmatory analysis of
subgroup of patients that received full treatment dur-
ation revealed that there was no significant difference
 INFECTIOUS DISEASES 5

between the two groups in terms of in-hospital

Duration of use not given. However significant difference in use of vasopressors at day 4 as compared to day 1[vasopressin (difference from day 1 – 0.0008 ± 0.00289 vs 0.0033 ± 0.00492 units/kg/min; p ¼ .02) and nor-
Treatment group
(in days) [Range]

(IQR 10.0–22.0)
14 [IQR, 9–22]

8.3 (IQR ¼ 5)
9 (IQR 4–14)

11.82 ± 7.36
mortality.

19 [9–26]

[4–36]
15.0
Duration of hospital stay

–
The only RCT available that tried to evaluate the

a
effect of triple therapy on various clinical outcomes is by
Balakrishnan et al. [14]. The study included post-opera-

9.3 (IQR 3.7–19.5)

Control group (in

tive adult cardiac surgical patients with septic shock.

13 [IQR, 8–23]

12 (IQR 6–17)
days) [Range]

10.70 ± 6.39
14 [8–23]
Primary endpoint included vasopressor free days and

[2–27]
–

–
a

secondary endpoint was in-hospital mortality. Significant

reductions in the requirement of vasopressors at day 4,
[vasopressin (difference from day 1 – 0.0008 ± 0.00289 vs
Treatment group

4.5 (IQR 4.0–6.0)

0.0033 ± 0.00492 units/kg/min; p ¼ .02) and noradren-

75.72 ± 30.29
[37–169.3]
18.3 ± 9.8

[20–140]
Duration of vasopressor use

aline (difference from day 1 – 0.0283 ± 0.040 vs

84.2
–

–
b

0.023 ± 0.035 lg/kg/min; p ¼ .01)] were observed in the

(in hours)[Range]

treatment group as compared to the control group.

Serum procalcitonin (PCT) levels on day 3 (68.11 ± 33.64
2.0 (IQR 1.0–3.0)
Control group

96.13 ± 40.50
[32.6–105.9]

vs 33.2 ± 27.55 ng/mL; p ¼ .02) and day 4 (70.03 ± 29.74

54.9 ± 28.4

[30–200]
62.5

vs 26.3 ± 23.08 ng/mL; p ¼ .001) were also significantly

–

–
b

lower in treatment group as compared to the controls.

However, there was no difference in the SOFA score and
in-hospital mortality between the 2 groups. The study
Treatment
group (%)

18.3

was, however, limited by the fact that it included only

40
–

–
–

–
a
30-day mortality

post-operative cardiac surgical patients from a single

centre and the sample size was small consisting of only
24 cases randomised into 2 groups which was inad-
group (%)
Control

17.5

equate for assessing the difference in the secondary

42
–

–
–

–
a

end-point of in-hospital mortality.

Not mentioned as study reported to have inadequate sample size for difference in in-hospital mortality.

Sadaka et al. [18] in a retrospective study found that

the use of ascorbic acid, thiamine, and steroids (ATS) in
Treatment
group (%)

16.6
40.4

patients with septic shock (SS) was associated with

8.5

17
29

52
24
In hospital mortality

adrenaline (difference from day 1 – 0.0283 ± 0.040 vs 0.023 ± 0.035 lg/kg/min; p ¼ .01)].

lower ICU mortality (9.6% vs 42%, p ¼ .004), but the

overall hospital mortality (29% vs 45%, p ¼ .2) was not
statistically significant compared to the no-ATS group.
group (%)
Control

40.4

18.3
40.4

Duration of vasopressor use was significantly higher in

39
45

28
–
a
Table 3. Comparison of the study data with previous studies.

the patients who received triple therapy, (median: IQR

4.5: 4.0–6.0 vs 2.0: 1.0–2.0, p ¼ .001). This study had sev-
Randomised controlled trial

Randomised controlled trial

eral limitations including a small sample size, the obser-

Design of study

vational methodology, inclusion of non-consecutive

Retrospective

Retrospective
Retrospective

Retrospective
Retrospective

Descriptive

patients, and the study being from a single centre. In

addition, the triple therapy combination was prescribed
by some physicians and not others which resulted in a
selection bias. ICU mortality but not hospital mortality
difference reached statistical significance.
Total patients

Masood et al. [19] conducted a descriptive case series

1144

100
94
24

94

99
62

50

study to study the effect of triple therapy in early wean-

ing (within 48 h) from vasopressor support in 50 patients
Balakrishnan et al

with septic shock. Eighty-four percent were successfully

Masood et al.
Present study
Sadaka et al.
Litwak et al.

weaned off vasopressors within 48 h. Median days in the

Marik et al.

Shin et al.

Kim et al.

ICU were reported as 8.3 (interquartile range (IQR) ¼ 5).

The ICU mortality was observed at 52% (N ¼ 26). This
b
a
6 S. J. WANI ET AL.
Table 4. Ongoing registered clinical trials assessing the role of triple therapy in sepsis.
Name of trial
Vitamin C, thiamine and steroids in sepsis
(VICTAS) [40]
The vitamin C, hydrocortisone and thiamine in
patients with septic shock trial (VITAMINS) [41]
Ascorbic acid, corticosteroids, and thiamine in sepsis
(ACTS) trial [42]
Hydrocortisone, Vitamin C, and thiamine for the
treatment of sepsis and septic shock
(HYVCTTSSS) [43]
The effect of Vitamin C, thiamine and
hydrocortisone on clinical course and outcome in
patients with severe sepsis and septic shock [44]
Metabolic resuscitation using ascorbic acid,
thiamine, and glucocorticoids in sepsis
(ORANGES) [45]
Evaluation of hydrocortisone, vitamin C and
thiamine for the treatment of septic shock
(HYVITS) [46]
Steroids, thiamine, and Vitamin C in septic shock
(STACSS) [47]
Thiamine, Vitamin C and hydrocortisone in the
treatment of septic shock [48]
ATESS Trial [49]
study was also limited by a small sample size and the
descriptive design precluded randomisation.
In our study, we observed that in patients who
received the triple combination, the duration of vaso-
pressor use was significantly less in comparison to the
control group. The mean vasopressor duration was
(96.13 ± 40.50 h in control group vs 75.72 ± 30.29 h in
treatment group, p value¼ .01) (Figure 1). It has been
observed in literature that the mean duration of vaso-
pressor use in patients with septic shock varies between
72 and 120 h [26–28].
We also observed that the lactate clearance was bet-
ter in the treatment group as compared to the control
group (41.81% in control group vs 56.83% in treatment
group) which is obviously related to the lower duration
of the use of vasopressors and consequent normalisation
of the target blood pressure as well as use of thiamine
in the treatment group compared to the control group.
Mean lactate on day 1 (control group 4.95 ± 2.39 vs
4.17 ± 2.46 in treatment group) which was not signifi-
cant. However, on day 3 mean serum lactate levels were
2.88 ± 1.70 in the control group vs 1.80 ± 0.53 in treat-
ment group, the difference being statistically significant.
Thiamine administration within 24 h of admission in
patients with septic shock has previously also been
reported to be associated with improved lactate clear-
ance [29].
14(28%) patients in control group and 12(24%)
patients in treatment group were offered mechanical
ventilation but only 3(6%) patients in each group agreed
to receive the same due to refusal by patients/
Country Trial Identifier
USA NCT03509350
Australia and New Zealand NCT03333278
USA NCT03389555
China NCT03258684
Slovenia NCT03335124
USA NCT03422159
Qatar NCT03380507
India CTRI/2018/04/013384
USA NCT03540628
South Korea NCT03756220
attendants. This could have affected the overall mortality
of the patients in both groups. However such patients
were equally distributed in both the groups.
Thiamine functions as a coenzyme for various bio-
pathways such as glucose metabolism, Krebs cycle, and
adenosine triphosphate (ATP) synthesis [30]. Thiamine
deficiency is also common in critically ill patients and
can lead to lactic acidosis due to inability of pyruvate to
enter the Krebs cycle [30]. In critically ill patients having
a baseline deficiency of thiamine, supplementation of
thiamine significantly decreases lactate levels [31].
Use of steroids in sepsis has yielded conflicting
results. Hydrocortisone is included in the Surviving
Sepsis Campaign guidelines for the treatment of refrac-
tory septic shock [32]. Glucocorticoids prevent the induc-
tion of nitric oxide synthase, that can cause relaxation of
the vascular smooth muscle resulting in vasodilation
and hypotension [33]. Glucocorticoids can also potenti-
ate the effects of catecholamines via glucocorticoid
receptors on vascular smooth muscle cells [34]. In vascu-
lar endothelial cells, glucocorticoids suppress the pro-
duction of vasodilators such as prostacyclins and nitric
oxide [34]. As an anti-inflammatory agent, steroids can
also help mitigate the inflammatory responses and rela-
tive adrenal insufficiency during septic shock [35–36].
Vitamin C functions as a cofactor for biosynthesis of
neurotransmitters such as noradrenaline, cortisol, and
vasopressin, and produces anti-inflammatory effects in
the body [30]. Plasma vitamin C levels have been seen
to be significantly reduced in patients with sepsis and
septic shock, which can contribute to increased capillary

permeability, hypotension, oxidative organ injury, and
impaired immunity [30,37,38]. Treatment of vitamin c
deficiency has been shown to decrease SOFA scores,
procalcitonin and C-reactive protein which can translate
to decreases in organ failure [39].
Our study is limited by the fact that it was a single
centre open label study with a small sample size but its
strength lay in its being a randomised prospective trial
from a geographical area with high prevalence of anti-
microbial resistance and mortality from sepsis. There are
a number of ongoing clinical trials of thiamine, ascorbic
acid, and corticosteroids in sepsis, the results of which
are not out yet (Table 4) [40–49]. The results of these tri-
als will further enlighten us about the potential benefits
of triple therapy in clinical practice in patients
with sepsis.
In conclusion, our results suggest incorporating vita-
min C, hydrocortisone, and thiamine into standard care
of sepsis and septic shock do not improve patient out-
come in terms of in hospital and 30-day mortality, hos-
pital stay and improvement in indices of severity.
However since we found that this combination resulted
in reduction in duration of vasopressor use and better
lactate clearance, we recommend that multicenter, dou-
ble blind, randomised controlled trials with larger sam-
ple size be conducted to assess for the potential
benefits of this therapy in terms of duration of vasopres-
sor use and lactate clearance.
Disclosure statement
The study was supported by research grant by SKIMS, Soura.
The authors declare no conflicts of interest related to
the study.
Take-home message
A combination of vitamin C, hydrocortisone, and thiamine added
to standard care of sepsis and septic shock does not improve in
hospital or 30-day mortality. However, patients who receive the
combination have significantly reduced duration of vasopressor
usage and a better lactate clearance.
Tweet
Combination of vitamin C, steroids and thiamine added to stand-
ard care does not improve mortality but reduces vasopressor use.
Funding
This work was supported by Sheri Kashmir Institute of Medical
Sciences, Srinagar, J&K, India.
INFECTIOUS DISEASES 7
References
[1] Gustot T. Multiple organ failure in sepsis: prognosis and
role of systemic inflammatory response. Curr Opin Crit
Care. 2011;17(2):153–159.
[2] Adhikari NK, Fowler RA, Bhagwanjee S, et al. Critical care
and the global burden of critical illness in adults. Lancet.
2010;376(9749):1339–1346.
[3] Kaukonen K-M, Bailey M, Suzuki S, et al. Mortality related
to severe sepsis and septic shock among critically ill
patients in Australia and New Zealand, 2000–2012. JAMA.
2014;311(13):1308–1316.
[4] Dombrovskiy VY, Martin AA, Sunderram J, et al. Rapid
increase in hospitalization and mortality rates for severe
sepsis in the United States: a trend analysis from 1993 to
2003. Crit Care Med. 2007;35(5):1244–1250.
[5] Padkin A, Goldfrad C, Brady AR, et al. Epidemiology of
severe sepsis occurring in the first 24 hrs in intensive care
units in England, Wales, and Northern Ireland. Crit Care
Med. 2003;31(9):2332–2338.
[6] Pavon A, Binquet C, Kara F, et al. Profile of the risk of death
after septic shock in the present era: an epidemiologic
study. Crit Care Med. 2013;41(11):2600–2609.
[7] Liu V, Escobar GJ, Greene JD, et al. Hospital deaths in
patients with sepsis from 2 independent cohorts. JAMA.
2014;312(1):90–92.
[8] Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural
history of the systemic inflammatory response syndrome
(SIRS). A prospective study. JAMA. 1995;273(2):117–123.
[9] Singer M, Deutschman CS, Seymour CW, et al. The Third
International consensus definitions for sepsis and septic
shock (Sepsis-3). JAMA. 2016;315(8):801–810.
[10] Silva E, Pedro M, Sogayar A, et al. Brazilian sepsis epidemio-
logical study (BASES study). Crit Care. 2004;8(4):R251–R260.
[11] Sales JA, David CM, Hatum R. Sepse Brasil: Estudo
Epidemiologico da Sepse em Unidades de Terapia
Intensiva Brasileiras. An epidemiological study of sepsis in
Intensive Care Units. Rev Bras Ter Intensiva. 2006;18:9–17.
[12] Todi S, Chatterjee S, Sahu S, et al. Epidemiology of severe
sepsis in India: an update. Crit Care. 2010;14(Suppl 1):P382.
[13] Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone,
Vitamin C and thiamine for the treatment of severe sepsis
and septic shock: a retrospective before after study. Chest.
2017;151(6):1229–1238.
[14] Balakrishnan M, Gandhi H, Shah K, et al. Hydrocortisone,
Vitamin C and thiamine for the treatment of sepsis and
septic shock following cardiac surgery. Indian J Anaesth.
2018;62(12):934–939.
[15] Shin TG, Kim YJ, Ryoo SM, et al. Early vitamin C and thia-
mine administration to patients with septic shock in emer-
gency departments: Propensity score-based analysis of a
before-and-after cohort study. J Clin Med. 2019;8(1):102.
[16] Kim W-Y, Jo E-J, Eom JS, et al. Combined vitamin C, hydro-
cortisone and thiamine therapy for patients with severe
pneumonia who were admitted to the intensive care unit:
propensity score based analysis of a before after cohort
study. J Crit Care. 2018;47:211–218.
8 S. J. WANI ET AL.
[17] Jane JL, Nam Cho H, Bryant N, Moussavi K, et al. Vitamin C,
hydrocortisone, and thiamine for the treatment of severe
sepsis and septic shock: a retrospective analysis of real-
world application. JCM. 2019;8(4):e478.
[18] Sadaka F, Grady J, Organti N, et al. Ascorbic acid, thiamine,
and steroids in septic shock: propensity matched analysis. J
Intensive Care Med. [cited 2019 Jul 17]; [5 p.]. DOI:10.1177/
0885066619864541
[19] Masood H, Burki AM, Sultan A, et al. Effect of intravenous
vitamin C, thiamine, and hydrocortisone (the metabolic
resuscitation protocol) on early weaning from vasopressors
in patients with septic shock. A descriptive case series
study. Cureus. 2019;11(6):e5016.
[20] Kellum JA, Lameire N, KDIGO AKI Guideline Work Group.
Diagnosis, evaluation and management of acute kidney
injury: a KDIGO summary (Part 1). Crit Care. 2013;17(1):204.
[21] Perl TM, Dvorak L, Hwang T, et al. Long term survival and
function after suspected gram negative sepsis. JAMA. 1995;
274(4):338–345.
[22] Nesseler N, Defontaine A, Launey Y, et al. Long term mor-
tality and quality of life after septic shock: a follow up
observational study. Intensive Care Med. 2013;39(5):
881–888.
[23] Sasse KC, Nauenberg E, Long A, et al. Long term survival
after intensive care unit admission with sepsis. Crit Care
Med. 1995;23(6):1040–1047.
[24] Prescott HC, Osterholzer JJ, Langa KM, et al. Late mortality
after sepsis: propensity matched cohort study. BMJ. 2016;
353:i2375.
[25] Ou S-M, Chu H, Chao P-W, et al. Long-term mortality and
major adverse cardiovascular events in sepsis survivors. A
nationwide population-based study. Am J Respir Crit Care
Med. 2016;194(2):209–217.
[26] Group CS. Hydrocortisone therapy for patients with septic
shock. N Engl J Med. 2008;358(2):111–124.
[27] Russell JA, Walley KR, Singer J, et al. Vasopressin versus
norepinephrine infusion in patients with septic shock. N
Engl J Med. 2008;358(9):877–887.
[28] Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of
early vasopressin vs norepinephrine on kidney failure in
patients with septic shock: the VANISH randomized clinical
trial. JAMA. 2016;316(5):509–518.
[29] Woolum JA, Abner EL, Kelly A, et al. Effect of thiamine
administration on lactate clearance and mortality in
patients with septic shock. Crit Care Med. 2018;46(11):
1747–1752.
[30] Amrein K, Straaten H, Berger MM. Vitamin therapy in critic-
ally ill patients: focus on thiamine, vitamin C, and vitamin
D. Intensive Care Med. 2018;44(11):1940–1944.
[31] Donnino MW, Andersen LW, Chase M, et al. Randomized,
double-blind, placebo-controlled trial of thiamine as a
metabolic resuscitator in septic shock: a pilot study. Crit
Care Med. 2016;44(2):360–367.
[32] Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis
campaign: international guidelines for management of sep-
sis and septic shock. Crit Care Med. 2017;45(3):486–552.
[33] Rees DD, Cellek S, Palmer RM, et al. Dexamethasone pre-
vents the induction by endotoxin or a nitric oxide synthase
and the associated effects on vascular tone: an insight into
endotoxin shock. Biochem Biophys Res Commun. 1990;
173(2):541–547.
[34] Yang S, Zhang L. Glucocorticoids and vascular reactivity.
Curr Vasc Pharmacol. 2004;2(1):1–12.
[35] De Kruif MD, Lemaire LC, Giebelen IA, et al. Prednisolone
dose-dependently influences inflammation and coagulation
during human endotoxemia. J Immunol. 2007;178(3):
1845–1851.
[36] Siraux V, De Backer D, Yalavatti G, et al. Relative adrenal
insufficiency in patients with septic shock: comparison of
low-dose and conventional corticotropin tests. Crit Care
Med. 2005;33(11):2479–2486.
[37] Long C, Maull K, Krishnan R, et al. Ascorbic acid dynamics
in the seriously ill and injured. J Surg Res. 2003;109(2):
144–148.
[38] Carr AC, Shaw GM, Fowler AA, et al. Ascorbate-dependent
vasopressor synthesis: a rationale for vitamin C administra-
tion in severe sepsis and septic shock? Crit Care. 2015;
19(1):418.
[39] Fowler A, Syed A, Knowlson S, et al. Phase I safety trial of
intravenous ascorbic acid in patients with severe sepsis. J
Transl Med. 2014;12(1):32.
[40] Vitamin C, thiamine and steroids in sepsis (VICTAS).
[Accessed 2019 Dec 31]. Available from www.clinicaltrials.
gov.
[41] The vitamin C, hydrocortisone and thiamine in patients
with septic shock trial (VITAMINS). [Accessed 2019 Dec 31].
Available from www.clinicaltrials.gov.
[42] Ascorbic acid, corticosteroids, and thiamine in sepsis
(ACTS) trial. [Accessed 2019 Dec 31]. Available from www.
clinicaltrials.gov.
[43] Hydrocortisone, vitamin C, and thiamine for the treatment
of sepsis and septic shock (HYVCTTSSS). [Accessed 2019
Dec 31]. Available from www.clinicaltrials.gov.
[44] The effect of vitamin C, thiamine and hydrocortisone on
clinical course and outcome in patients with severe sepsis
and septic shock. [Accessed 2019 Dec 31]. Available from
www.clinicaltrials.gov.
[45] metabolic resuscitation using ascorbic acid, thiamine, and
glucocorticoids in sepsis (ORANGES). [Accessed 2019 Dec
31]. Available from www.clinicaltrials.gov.
[46] Evaluation of hydrocortisone, vitamin C and thiamine for
the treatment of septic shock (HYVITS). [Accessed 2019 Dec
31]. Available from www.clinicaltrials.goc.
[47] Steroids, thiamine, and vitamin C in septic shock (STACSS).
[Accessed 2019 Dec 31]. Available from www.clinicaltrials.
gov.
[48] Thiamine, vitamin C and hydrocortisone in the treatment
of septic shock. [Accessed 2019 Dec 31]. Available from
www.clinicaltrials.gov.
[49] ATESS Trial. [Accessed 2019 Dec 31]. Available from www.
clinicaltrials.gov.in.