High Dose Intravenous Ascorbic Acid in Severe Sepsis

The Efficacy of Intravenous Ascorbic Acid in Patients With Severe Sepsis

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.

1. Recent research has described the therapeutic benefits associated with ascorbic acid treatment for sepsis.
2. 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.
3. 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.

Study Overview

• Status: Terminated
• Conditions: Sepsis
• Intervention / Treatment: Other: Normal Saline; Drug: Ascorbic Acid

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Delaware
    • Newark, Delaware, United States, 19718
      • Chrisitana Care Health System-Christiana Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients with:

1. A suspected or confirmed infection with an order for intravenous antibiotics or antivirals
2. The presence of acute sepsis-induced organ dysfunction

Definition of organ dysfunction:

1. Arterial hypoxemia [PaO2 /FiO2 < 300]
2. Hypotension [systolic blood pressure (SBP) < 90 mmHg or SBP decrease > 40 mmHg]
3. Lactic acidosis [lactate > 2.5 mmol/L]
4. Acute kidney injury [creatinine >2.0 or urine output < 0.5 ml/kg/hr for >2 hours despite fluid resuscitation]
5. Thrombocytopenia [platelet count < 100,000]
6. Acute coagulopathy [international normalized ratio (INR) > 1.5]
7. Hepatic failure [bilirubin > 2 mg/dL].
8. Predisposition, Infection, Response, and Organ Failure (PIRO) score ≥ 10

Exclusion Criteria:

1. Age < 18 years
2. Pregnancy or breastfeeding
3. Requirement for immediate surgery within the treatment protocol timeframe
4. Inability to obtain written informed consent from subject or surrogate
5. Patient to receive comfort measures only

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: High dose IV ascorbic acid; 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
PLACEBO_COMPARATOR: Placebo; The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours.	Other: Normal Saline

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Christiana Care Health Services
• Investigators: Principal Investigator: Jamie Rosini, PharmD, Christiana Care Health Services

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (ACTUAL): October 8, 2017
• Study Completion (ACTUAL): November 23, 2017

Study Registration Dates

• First Submitted: March 18, 2016
• First Submitted That Met QC Criteria: April 11, 2016
• First Posted (ESTIMATE): April 12, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 16, 2021
• Last Update Submitted That Met QC Criteria: January 28, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: 603204