Vitamin C, Vitamin B1 and Steroid in Sepsis

Study Overview
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Brief Summary
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A randomized controlled trial to test the synergic modulation effect of vitamin C, thiamine and hydrocortisone in patients with severe sepsis or septic shock.

Detailed Description
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Management of sepsis bases on three components: infection control, haemodynamic stabilization and modulation of the septic response. Many clinical trials conducted agents to block the inflammatory cascade, such as corticosteroids, anti-endotoxins antibodies, tumor necrosis factor (TNF) antagonists, interleukin-1-receptor antagonists, and so on, but none has proven effective to date. A safe, effective, ready available therapy is desperately required. Thiamine is a key co-factor for pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase. All the three enzymes are required to complete Krebs Cycle to prevent from lactate production. Previous studies have found thiamine deficiency to be prevalent in septic shock and other critically ill conditions. One pilot study also proved patients with septic shock and baseline thiamine deficiency would have significant lower lactate level at 24 hours after administration of thiamine. HYPRESS (hydrocortisone for Prevention of Septic Shock) study failed to demonstrate an outcome benefit from a hydrocortisone infusion in patients with sepsis. Vitamin C is a potent antioxidant that directly scavenges oxygen free radicals, can restores other cellular antioxidants and plays a role in preserving endothelial function and microcirculatory flow as well. Though previous studies suggested that hydrocortisone and vitamin C alone have little impact on the clinical outcome of patients with sepsis. Vitamin C and hydrocortisone have many overlapping and synergic pathophysiologic effects in sepsis. Both drugs are required for the synthesis of catechlamines and increase vasopressor sensitivity. Both drugs can down-regulating the production of proinflammatory mediators, increase tight junctions between endothelial and epithelial cells, preserve endothelial function and microcirculatory flow. Marik et al published their study in CHEST (June 2017) resulting the benefits of combination of Vitamin B1, Vitamin C and hydrocortisone to severe sepsis and septic shock. However, small sample size and some bias due to imbalanced baseline and study method could confound the results. Herein, we would like to lead a randomized controlled trial to test the synergic modulation effect of vitamin C, thiamine and hydrocortisone in patients with severe sepsis or septic shock.

Official Title
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Effects of Vitamin C, Thiamine and Hydrocortisone in Septic Shock: a Randomized, Controlled Trial

Conditions
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Sepsis, Severe

Intervention / Treatment
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* Drug: Ascorbic acid-Vitamin B1-Hydrocortisone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: aged equal or over 20 admitted to MICU due to severe sepsis or septic shock Exclusion Criteria: Patients who are pregnant known history of Vitamin C , Vitamin B or hydrocortisone (or other equivalent products) allergy

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: double blind, randomized-controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABC group (Ascorbic acid-Vitamin B1-Hydrocortisone) group<br>patients in study group, so called ABC (Ascorbic acid-Vitamin B1-Hydrocortisone) group, would receive intravenous Thiamine (200mg in 50 mL of 0.9% normal saline and was administered as a 30-min infusion every 12 hours for 4 days or until ICU discharge), Vitamin C (1.5g mixed in a 100-mL solution of normal saline and was administered as an infusion over 30 to 60 min every 6 hours for four days or until ICU discharge) as well as hydrocortisone 50mg every 6 hours (or other equivalent products) for 7 days | Drug: Ascorbic acid-Vitamin B1-Hydrocortisone<br>* intravenous Thiamine (200mg in 50 mL of 0.9% normal saline and was administered as a 30-min infusion every 12 hours for 4 days or until ICU discharge), plus Vitamin C (1.5g mixed in a 100-mL solution of normal saline and was administered as an infusion over 30 to 60 min every 6 hours for four days or until ICU discharge) as well as hydrocortisone 50mg every 6 hours (or other equivalent products) for 7 days<br>|
| Placebo Comparator: normal saline group<br>patients would receive 50mL 0.9% normal saline, 100 mL 0.9% normal saline with the same infusion rate and hydrocortisone dependent on the discretion of the attending physician | Drug: Placebo<br>* patients would receive 50mL 0.9% normal saline, 100 mL 0.9% normal saline with the same infusion rate and hydrocortisone dependent on the discretion of the attending physician<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint was the hospital survival. | hospital survival | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| duration of vasopressor therapy | duration of vasopressor therapy | 72 hours | 
| requirement for renal replacement therapy in patients with acute kidney injury (AKI) | requirement for renal replacement therapy in patients with acute kidney injury (AKI) | 72 hours | 
| ICU length of stay (LOS) | ICU length of stay (days) | 4 days | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | APACH II score (total 0 100) is a score to evaluate the mortality rate of ICU patients, higher values represent a worse outcome. It includes: (A) PaO2 (depending on FiO2) Temperature (rectal) Mean arterial pressure pH arterial Heart rate Respiratory rate Sodium (serum) Potassium (serum) Creatinine Hematocrit White blood cell count (B) age points (score: 0 6) (C) chronic health problems (liver cirrhosis, dialysis, COPD, congestive heart failure, immunocompromised) | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | PaO2 (depending on FiO2): mmHg | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | Temperature ( Celsius degrees) | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | Mean arterial pressure : mmHg | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | pH arterial | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | Heart rate: bpm | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | Respiratory rate: 1/min | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | Sodium (serum): mmol/L | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | Potassium (serum): mmol/L | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | Creatinine: mg/dL | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | Hematocrit: % | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | White blood cell count: 10 3/μL | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | age: years | 72 hours | 
| change of Acute Physiology And Chronic Health Evaluation II (APACH II) score over the first 72 hours | chronic health problems (liver cirrhosis, dialysis, COPD, congestive heart failure, immunocompromised): None: 0 point Non-surgical: 5 points Emergent operation: 5 points | 72 hours | 
| Sequential Organ Failure Assessment score (SOFA score) over the first 72 hours | PaO₂: mm Hg | 72 hours | 
| Sequential Organ Failure Assessment score (SOFA score) over the first 72 hours | Platelets: ×10³/µL | 72 hours | 
| Sequential Organ Failure Assessment score (SOFA score) over the first 72 hours | Glasgow Coma Scale: points 15: 0 13-14: +1 10-12: +2 6-9: +3 <6: +4 | 72 hours | 
| Sequential Organ Failure Assessment score (SOFA score) over the first 72 hours | Bilirubin: mg/dL | 72 hours | 
| Sequential Organ Failure Assessment score (SOFA score) over the first 72 hours | Mean arterial pressure: mmHg | 72 hours | 
| Sequential Organ Failure Assessment score (SOFA score) over the first 72 hours | Creatinine: mg/dL | 72 hours |