High Dose Intravenous Ascorbic Acid in Severe Sepsis

Study Overview
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Brief Summary
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Despite an organized treatment approach outlined in expert-consensus guidelines for sepsis with fluid resuscitation to treat hypovolemia, antibiotics to target the infectious insult, and vasopressors for hypotension, mortality rates for sepsis remain high and the incidence continues to rise, making sepsis the most expensive inpatient disease. Recent research has described the therapeutic benefits associated with ascorbic acid treatment for sepsis. Researchers objectives are to perform a randomized-controlled clinical trial investigating the ability of ascorbic acid(vitamin C) administration to decrease organ dysfunction in severe sepsis. The widespread occurrence of microvascular dysfunction in sepsis leading to tissue hypoxia, mitochondrial dysfunction, and adenosine triphosphate (ATP) depletion, gives rise to organ failure. Patients with organ failure and sepsis (severe sepsis) are at a higher risk of death than patients with organ failure alone. Critically ill patients may have an increased requirement for ascorbic acid in sepsis and these patients frequently have levels below normal. Ascorbic acid administration, has been shown to correlate inversely with organ failure (human literature) and directly with survival (animal studies). 4,5 Intravenous ascorbic acid therapy decreases organ failure by providing a protective effect on several microvascular functions including improving capillary blood flow, decreasing microvascular permeability, and improving arteriolar responsiveness to vasoconstrictors. Defining the utility of novel agents to augment researchers care for severe sepsis is an important task as investigators continue the institutional focus on sepsis care.

Official Title
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The Efficacy of Intravenous Ascorbic Acid in Patients With Severe Sepsis

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Ascorbic Acid
* Other: Normal Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with: A suspected or confirmed infection with an order for intravenous antibiotics or antivirals The presence of acute sepsis-induced organ dysfunction Definition of organ dysfunction: Arterial hypoxemia [PaO2 /FiO2 < 300] Hypotension [systolic blood pressure (SBP) < 90 mmHg or SBP decrease > 40 mmHg] Lactic acidosis [lactate > 2.5 mmol/L] Acute kidney injury [creatinine >2.0 or urine output < 0.5 ml/kg/hr for >2 hours despite fluid resuscitation] Thrombocytopenia [platelet count < 100,000] Acute coagulopathy [international normalized ratio (INR) > 1.5] Hepatic failure [bilirubin > 2 mg/dL]. Predisposition, Infection, Response, and Organ Failure (PIRO) score ≥ 10 Exclusion Criteria: Age < 18 years Pregnancy or breastfeeding Requirement for immediate surgery within the treatment protocol timeframe Inability to obtain written informed consent from subject or surrogate Patient to receive comfort measures only

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: High dose IV ascorbic acid<br>Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. | Drug: Ascorbic Acid<br> <br> |
| Placebo Comparator: Placebo<br>The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours. | Other: Normal Saline<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Modified SOFA Score | Sequential Organ Failure Assessment (SOFA) Score included the degree of dysfunction of six organ systems (Respiratory, Cardiovascular, Liver, Renal, Coagulation, Neurologic. A modification of the SOFA includes the exclusion of the Liver function. Total score is reported, minimum score = 0 maximum score = 20. Higher scores indicate greater degree of dysfunction. | Baseline and 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified SOFA Score | Sequential Organ Failure Assessment (SOFA) Score included the degree of dysfunction of six organ systems (Respiratory, Cardiovascular, Liver, Renal, Coagulation, Neurologic. A modification of the SOFA includes the exclusion of the Liver function. Total score is reported, minimum score = 0 maximum score = 20. Higher scores indicate greater dysfunction. | at 72 Hours | 
| Ascorbic Acid Concentration at 32 Hours | Ascorbic Acid Concentration Normal Ascorbic Acid Range 0.4-2.0 mg/dL | 32 Hours | 
| ICU Length of Stay | ICU Length of Stay in Hours | Length of ICU stay up to 200 hours | 
| Hospital Length of Stay | From admission until discharge from ICU in days | From ICU admission through ICU discharge, up to 2 weeks | 
| Change in PIRO Score | PIRO consists of 4 assessments, Predisposition (scored 0-9), Infection (scored 0-4), Response (scored 0-6), and Organ Failure (scored 0-14) (PIRO). The total PIRO score is the sum of all subscores and ranges from 0-33 with higher scores indicating worse health. | Baseline and 72 hours | 
| Percentage of Participants Who Died |  | From initial hospital admission through discharge, up to 2 weeks. |