Vitamin C, Vitamin B1 and Steroid in Sepsis

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

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

Study Overview

• Status: Unknown
• Conditions: Sepsis, Severe
• Intervention / Treatment: Drug: Ascorbic acid-Vitamin B1-Hydrocortisone; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• Taiwan
  • Taipei County, Taiwan, 100
    • Far Eastern Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ABC group (Ascorbic acid-Vitamin B1-Hydrocortisone) group; 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; 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
PLACEBO_COMPARATOR: normal saline group; 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; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Far Eastern Memorial Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 3, 2019
• Primary Completion (ANTICIPATED): December 31, 2020
• Study Completion (ANTICIPATED): December 31, 2020

Study Registration Dates

• First Submitted: December 11, 2018
• First Submitted That Met QC Criteria: July 29, 2019
• First Posted (ACTUAL): July 31, 2019

Study Record Updates

• Last Update Posted (ACTUAL): December 6, 2019
• Last Update Submitted That Met QC Criteria: December 4, 2019
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Protective Agents; Micronutrients; Vitamins; Antioxidants; Vitamin B Complex; Hydrocortisone; Ascorbic Acid; Thiamine
• Other Study ID Numbers: 107133-F

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD are not to be shared with other researchers

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No