Table 1 Characteristics of included studies
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 |