Ascorbic Acid and Thiamine Effect in Septic Shock

Study Overview
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Brief Summary
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The aim of this study is to evaluate the efficacy of early metabolic resuscitation with combination therapy using vitamin C and thiamine in improving organ function and survival in patients with septic shock.

Detailed Description
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Sepsis is a complex disease involving life-threatening organ dysfunction caused by a dysregulated host response to infection and is still associated with unacceptably high mortality. Sepsis management should be undertaken as a medical emergency and focused on timely intervention, including early identification and treatment of infection through appropriate antimicrobial therapy and source control when applicable as well as reversing hemodynamic instability through fluid resuscitation and vasopressor use if necessary. Despite these supportive therapies, morbidity and mortality have remained high, suggesting the need for adjuvant therapies for inflammatory and oxidative stress in patients with sepsis; however, no agents have been proven to definitely improve survival. Vitamin C plays a role in mediating inflammation through antioxidant activities and is also important as a cofactor/co-substrate for the synthesis of endogenous adrenaline, cortisol, and vasopressin. Recently, several clinical trials have reported the positive effects of vitamin C on outcomes in sepsis or septic shock. During sepsis, vitamin C prevents neutrophil-induced lipid oxidation and protects against the loss of the endothelial barrier. Early intravenous supplementation is therefore needed to limit loss of microcirculation and oxidation of lipids. Thiamine is also a key cofactor for glucose metabolism, the generation of ATP (adenosine triphosphate), and the production of NADPH. Considering acute consumption in the hypermetabolic state, thiamine supplementation might be a reasonable therapeutic adjunct for patients with sepsis and was added to reduce the risk of renal oxalate crystallization. These findings led to a recent before-and-after study showing that treatment of sepsis with a combination of vitamin C, hydrocortisone, and thiamine prevented organ dysfunction and reduced the mortality rate. The aim of this study is to evaluate the efficacy of early metabolic resuscitation with combination therapy using vitamin C and thiamine in improving organ function and survival in patients with septic shock.

Official Title
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Combination Therapy of Vitamin C and Thiamine for Septic Shock: Multi-center, Double-blinded, Randomized, Controlled Study

Conditions
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Septic Shock, Sepsis

Intervention / Treatment
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* Drug: Combination therapy of vitamin C and thiamine
* Drug: Normal saline solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (> 18 years) Septic shock: sepsis with persisting hypotension requiring vasopressors to maintain a mean arterial pressure ≥65 mm Hg and a serum lactate level >2 mmol/L despite adequate volume resuscitation. Sepsis is defined as clinically suspected or confirmed infection with acute organ failure identified as an acute change in total SOFA score with 2 points or more. Exclusion Criteria: Transferred patients from other hospitals after application of vasopressors or mechanical ventilation Patients who signed a Do not attempt resuscitation order or who had set limitations on invasive care Patients who have a terminal, unresponsive illness and survival discharge is not expected (metastatic terminal cancer, etc.) Patients who experienced cardiac arrest before enrollment or when death is anticipated within 24 hours despite maximal treatment Patients who take more than 1g of Vitamin C per day before enrollment or who take supplemental thiamine Pregnant woman Known Glucose-6-phosphate dehydrogenase deficiency Patients with a history of hypersensitivity to vitamin C or thiamine Known Mediterranean anemia Known hyperoxaluria Known cystinuria Acute gout attack Known oxalate renal stone Patients who meet the inclusion criteria 24 hours after emergency department arrival or when enrollment is delayed more than 24 hours after diagnosis of septic shock Inability or refusal of a subject or legal surrogate to give informed consent

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 89 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: Multi-center, Double-blinded, Randomized, Controlled Study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Combination therapy of vitamin C and thiamine for 2 days. | Drug: Combination therapy of vitamin C and thiamine<br>* Vitamin C (50 mg/kg up to 3 g, every 12 hours) and thiamine (200 mg every 12 hours) intravenously administered mixed in 50 mL solution bags of normal saline for 2 days<br>* Other names: Thiamine Injection;|
| Placebo Comparator: Control<br>Normal Saline Solution | Drug: Normal saline solution<br>* Normal saline solution in a volume to match the treatment components administered mixed in 50 mL solution bags of normal saline for 2 days<br>* Other names: 0.9% NaCl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delta Sequential Organ Failure Assessment (SOFA) score | 72-hour change in SOFA score, which reflected recovery from organ failure (delta SOFA = SOFA at enrollment - SOFA after 72 hours) | Enrollment to 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day mortality | The number of participants who did not survive until Day 28 will be compared between the treatment and the control group | Day 28 | 
| 7-day mortality (early death) | The number of participants who did not survive until Day 7 will be compared between the treatment and the control group | Day 7 | 
| 90-day mortality | The number of participants who did not survive until Day 90 will be compared between the treatment and the control group | Day 90 | 
| Time to death | Days until death | Enrollment to Day 28 | 
| In-hospital death | The number of participants who did not survive at hospital discharge will be compared between the treatment and the control group | Up to 12 weeks | 
| Intensive care unit death (ICU) death | The number of participants who did not survive at ICU discharge from the first index ICU admission will be compared between the treatment and the control group | Up to 12 weeks | 
| Time to Shock reversal | Days from enrollment to shock reversal until Day 14. Shock reversal is defined as discontinuation of all vasopressors and mean arterial pressure is maintained at 60 mmHg or more for more than 24 hours. | Enrollment to Day 14 | 
| Vasopressor free days | Days not receiving any vasopressor | Enrollment to Day 14 | 
| Ventilator free days | Days not receiving mechanical ventilation | Enrollment to Day 14 | 
| Ventilator duration | Days receiving mechanical ventilation during hospital stay | Up to 12 weeks | 
| Renal replacement therapy (RRT) free days | Days not receiving Renal replacement therapy | Enrollment to Day 14 | 
| New use of renal replacement therapy (RRT) | The number of participants who receive RRT during hospital stay will be compared between the treatment and the control group | Up to 12 weeks | 
| New onset or aggravation of acute kidney injury (AKI) | The number of participants who suffer from new onset or aggravation of AKI will be compared between the treatment and the control group | Enrollment to Day 14 | 
| Length of ICU stay | Number of days in the ICU during hospital admission | Up to 12 weeks | 
| ICU free day | Days not being in the ICU | Enrollment to Day 14 | 
| Length of hospital stay | Number of days in the hospital during hospital admission | Up to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Septic shock, Sepsis, Vitamin C, Thiamine