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Table 1 Characteristics of included studies

From: Hydrocortisone, ascorbic acid, and thiamine (HAT) for sepsis and septic shock: a meta-analysis with sequential trial analysis

References Country Inclusion criteria Exclusion criteria Group Samples Age Sex (male/female) Intervention protocol Outcomes Authors’ conclusions
Moskowitz [13] United States 1. Age: ≥ 18 years
2. Septic shock
1. Allergic to study drug components
2. Had a clinical indication for the study drugs
3. Had kidney stones last year
4. Had G6PD deficiency or hemochromatosis
5. Receiving RRT
HAT 101 68.9 57/44 Ascorbic acid (1.5 g) and thiamine (100 mg): mixed in 100 mL of normal saline and administered intravenously every 6 h for 4 days or discharge from ICU
Hydrocortisone: 50 mg/1 ml IV push every 6 h for 4 days or discharge from ICU
Primary outcome:
1. Change in SOFA score between enrollment and 72 h
Secondary outcomes:
1. All-cause mortality over 30 day
2. Kidney failure
3. Ventilator-free days
4. Shock-free days
5. Incidence of delirium
6. ICU-free days
7. All-cause mortality to ICU discharge
8. All-cause mortality to hospital discharge
9. Survivors discharged home
The HAT therapy was not supported routine use for patients with septic shock
Control 99 67.7 54/45 0.9% sodium chloride:
the same frequency and volume as above
Wani [11] India Sepsis and septic shock with a serum lactate level of > 2 mmol/l 1. Age: < 18 years
2. Pregnancy
HAT 50 65 28/22 Vitamin C: 1.5 g/100 ml IV piggyback every 6 h for 4 days or discharge from the hospital
Thiamine: 200 mg/50 ml IV piggyback every 12 h for 4 days or discharge from the hospital
Hydrocortisone: 50 mg every 6 h for 7 days or until ICU discharge followed by a taper over 3 days
Primary outcomes:
1. In-hospital mortality
Secondary outcomes:
1. 30-day mortality
2. Duration of hospital stay
3. Duration of vasopressor therapy
4. Lactate clearance
5. Change in serum lactate
6. The SOFA score over the first 4 days
Addition of HAT therapy into standard care of sepsis does not improve in-hospital or 30-day mortality. However, lower vasopressor requirement and faster lactate clearance is observed with treatment
Control 50 70 31/19
Iglesias [19] United States 1. age: ≥ 18 years
2. Sepsis or septic shock 24 h from admission
1. Pregnancy
2. DNR/DNI
3. Had a terminal end stage disease or G-6PD deficiency
4. Required surgery
5. HIV and a CD4 < 50 mm2
6. Transferred from another hospital
HAT 68 70 32/36 Ascorbic acid: 1.5 g/100 ml IV piggyback every 6 h for 4 days or discharge from ICU
Thiamine: 200 mg/50 ml IV piggyback every 12 h for 4 days or discharge from ICU
Hydrocortisone:
50 mg IV push every 6 h for 4 days or discharge from ICU
Primary outcome:
1. Duration of vasopressors
2. Change in SOFA score at 72 h
Secondary outcomes:
1. ICU mortality
2. Hospital mortality
3. Hospital LOS
4. ICU LOS
5. PCT clearance
6. Ventilator-free days
7. AKI
The HAT therapy significantly reduced the time to resolution of shock
Control 69 67 27/42 Sodium Chloride 0.9%: the same frequency and volume as above
Chang 2020 [12] China A primary diagnosis of sepsis or septic shock and PCT level ≥ 2 ng/ml 1. Age: < 18 years
2. Pregnancy
3. Patients with limitations of care
HAT 40 59.5 22/18 Vitamin C: 1.5 g every 6 h for 4 days or until ICU discharge
Thiamine: 200 mg every 12 h for 4 days or until ICU discharge
Hydrocortisone: 50 mg every 6 h for 7 days or until ICU discharge
Primary outcomes:
1. 28-days mortality
Secondary outcomes:
1. ICU LOS
2. Duration of vasopressors
3. New AKI after entering ICU
4. Change in SOFA score at 72 h
5. PCT clearance
6. Duration mechanical ventilation
7. Lactate clearance
The HAT therapy did not appear to reduce the 28-day mortality compared with placebo in patients with sepsis or septic shock
Control 40 63.7 21/19 Normal saline: 500 ml every day for 4 days, then 200 ml every day for 3 days
Fujii 2020 [22] Australia; Japan A primary diagnosis of septic shock at enrollment 1. Age < 18 years
2. Pregnancy
3. DNR
4. Imminent death
5. Diagnosis of septic shock longer than 24 h ago
6. Disease as indication or contraindication for any of the study drugs
HAT 107 61.9 68/39 Intravenous vitamin C
(1.5 g every 6 h), hydrocortisone
(50 mg every 6 h)
Thiamine
(200 mg every 12 h)
Primary outcome:
1. Time alive and free of vasopressors
Secondary outcomes:
1. 28-days mortality
2. 90-days mortality
3. ICU mortality
4. Hospital mortality
5. 28-days cumulative vasopressor-free days
6. 28-days RRT-free days
7. Change in SOFA score at day 3
8. 28-days ICU free days
In patients with septic shock, HAT treatment, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days
HAT does not lead to a more rapid resolution of septic shock
Control 104 61.6 65/39 IV hydrocortisone (50 mg every 6 h)
Hussein 2021 [23] Egypt 1. Adult
2. Septic shock
1. Pregnancy
2. Lactation
3. Refusal of attending
4. Had disease as indication or contraindication to any of the study drugs
5. Immunosuppressive medications
6. Oncology patients
7. DNR/DNI
HAT 47 65.81 25/22 Hydrocortisone
50 mg/6-h IV for 7 days or ICU discharge
vitamin C
1.5 g/6-h IV for 4 days or till ICU discharge
Thiamine
200 mg/12-h IV for 4 days or till ICU discharge
Primary outcome:
1. 28-day in-hospital mortality
2. ICU mortality
Secondary outcomes:
1. Duration on vasopressors
2. Weaning from mechanical ventilation
3. Improvement of organ function (Scr, AST, ALT)
4. Improvement of septic markers (TLC, CRP, lactate, PCT)
The HAT therapy showed a non-significant reduction in 28-day mortality and SOFA score but significantly lower shock time and duration on vasopressor use
Control 47 61.6 26/21 Hydrocortisone
50 mg/6-h IV for 7 days or till ICU discharge
Mohamed [20] India Adult non-pregnant patients with septic shock and within 6 h of initiation of inotropic support Patients with burns, limitations of care due to terminal illness or acute liver failure HAT 45 58.69 31/14 intravenous combination of
vitamin C: 1.5 g q6h
thiamine: 200 mg q12h
Hydrocortisone: 50 mg q6h first doses of the drugs administered within 6 h of onset of septic shock admission
Primary outcome:
1. All-cause mortality during inpatient stay
Secondary outcomes:
1. Time to shock reversal
2. Change in SOFA score over 72 h
3. Need for mechanical ventilation
4. Incidence of new onset of AKI
5. ICU and hospital LOS
HAT protocol did not reduce hospital mortality in patients with septic shock
HAT group has higher incidence of culture positivity for Klebsiella and Candida; significant reduction of hock reversal time, PCT level on day 3, PCT clearance at 72 h and ICU length of stay
Control 45 59.37 32/11 standard of care for septic shock
The use of hydrocortisone and
vitamin supplements in the control group was at the treating
physician’s discretion
Reddy 2020 [24] India Septic shock
Age ≥ 18 years
Pregnancy have new onset acute coronary syndrome H 7 55.4 3/4 Hydrocortisone:200 mg over 24 h infusion Primary outcome:
1. Time to shock reversal
Secondary outcomes:
1. time to vasopressor reduction (minutes) from SOFA(h) 4–3
H group has non-significantly longer shock reversal time than other groups
No significant difference in time to initiation of metabolic resuscitation among groups
Did not include the length of stay, ventilator-free days, and mortality in outcomes
HA 7 56.5 3/4 Hydrocortisone:200 mg over 24 h infusion
ascorbic acid 1.5 g IV q6 hour
HAT 7 53.8 4/3 Hydrocortisone:200 mg over 24 h infusion ascorbic acid 1.5 g IV q6 hour thiamine:200 mg IV q12 hours
Sevransky [21] US Age ≥ 18y
Acute respiratory and/or cardiovascular dysfunction caused by sepsis
ICU admission
Age < 18y
Weight < 40 kg
Organ dysfunction no longer present
Cardiovascular/respiratory organ failure caused by other disease
DNR, DNI
hospitalization > 30 days
indication or contraindication of any study drug
HAT 252 62 139/113 IV vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) within 4 h, then q6 hours thereafter up to 96 h, death, or discharge from the ICU Primary outcome:
1. The number of consecutive VVFDs in the first 30 days
Secondary outcomes
1. mortality within 30 days of randomization
2. ICU mortality
3. ICU and hospital LOS
4. ICU delirium- and coma-free days
5. Kidney replacement therapy-free days at day 30
6. Change in SOFA score (DAY4)
HAT compared with placebo, did not significantly increase ventilator- and vasopressor free days within 30 days
Control 249 61 134
/115
Matching placebos within 4 h, and then q6 hours thereafter up to 96 h, death, or discharge from the ICU
  1. RRT renal replacement therapy; DNR do not resuscitate; DNI do not intubate; CRF chronic renal failure; SOFA Sequential Organ Failure Assessment; LOS length of stay; TLC total leukocytic count; CRP C-reactive protein; PCT procalcitonin; AKI acute kidney injury; RRT renal replacement therapy; VVFDs ventilator and vasopressor free days