Ascorbic Acid (Vitamin C) Infusion in Human Sepsis

Study Overview
=================
Brief Summary
-----------------
The major goal of this project is to determine whether intravenously infused ascorbic acid is safe for use as a viable therapeutic strategy in adult humans with sepsis.

Detailed Description
-----------------
Evolving data from experimental animals strongly suggests that ascorbic acid potently interrupts multiple biological processes which lead to organ injury following onset of sepsis. Data presented below suggests that ascorbic acid potently attenuates lung injury produced by septic insults. Sepsis and septic shock secondary to bacterial and fungal blood stream infections are a leading cause of death in critically ill patients. At present, 28 day mortality in septic patients averages 40% in the best of ICUs. In sepsis, disseminated intravascular coagulation produces widespread systemic microvascular thrombosis that leads to multiple organ injury (i.e., lung, liver, kidney, intestinal, cardiovascular). Despite aggressive intravascular volume resuscitation and vasopressor support, appropriate antibiotic administration, and expert critical care management, mortality remains high. Only a single agent has been approved to disrupt progressive sepsis-associated microvascular thrombosis (activated protein C, [Drodrecogin Alpha, brand name: Xigris, Lilly]). No other non-antibiotic pharmaceutical agent is currently approved for use in sepsis. Activated protein C (APC) continuous infusion protocol spans a 96 hour period. APC infusion produces significant anticoagulation, and therefore the major risk from its use is hemorrhage. Thus, recent surgery, especially neurosurgical procedures, is a major contraindication to APC use. Finally, cost stands as an important issue for APC use. A 96 hour APC infusion in a 70 kg patient at VCUHS costs the patient over $33,000 (source VCUHS Pharmacy Services). Use of APC in sepsis remains controversial and has failed to achieve widespread acceptance. The goal of the current study is to determine the safety of ascorbic acid infusion in septic humans.

Official Title
-----------------
Ascorbic Acid (Vitamin C) Infusion in Human Sepsis

Conditions
-----------------
Sepsis, Septic Shock, Hypotension, Acute Lung Injury

Intervention / Treatment
-----------------
* Drug: Ascorbic Acid
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: systemic inflammatory response: fever (38°C or greater) or hypothermia (36°C or lower), tachypnea (20 breaths/min) or need for mechanical ventilation for an acute process, tachycardia (rate 90/min or more), white blood cell count ≥ 12,000 cells/mm3 or ≤ 4,000 cells/mm3 or more than 10% band forms. Presumed or Known Site of Infection: Purulent sputum, chest radiograph with new infiltrate, spillage of bowel contents, radiographic or physical examination evidence of an infected collection, white blood cells in a normally sterile body fluid, positive blood culture, evidence of infected mechanical hardware by physical, radiographic, or ultrasonographic evidence. Evidence of Dysfunction of One or More End Organs: cardiovascular dysfunction: mean arterial pressure 60 mm Hg or less, the need for vasopressors to maintain this pressure in the presence of adequate intravascular volume (central venous pressure 12 mmHg); respiratory failure: (arterial PO2-to-FiO2 ratio of less than 250 or less than 200 in the presence of pneumonia; renal dysfunction: Urine output ≤ 0.5 ml/kg/hr for 2 hours in the presence of adequate intravascular volume or doubling of the serum creatinine; hematologic dysfunction: thrombocytopenia ≤ 80,000 platelets/mm3 or 50% decrease from baseline during the acute illness; Unexplained metabolic acidosis: arterial pH ≤ 7.3 and a plasma lactate level higher than 2.5. Hepatic Dysfunction: Acute Serum transaminase elevation greater than five times normal. Informed Consent: Ability to obtain informed consent within 48 hours. Exclusion Criteria: Demographic Characteristics: Children (age < 18 years), pregnant women, prisoners, and other wards of the state are excluded from participation in this study. Informed Consent: Inability to obtain informed consent within 48 hours. Cognitive Impairment: In the absence of family or next of kin, if the investigators feel the patient is cognitively impaired, and unable to provide informed consent, the patient will not be accessed to the study. Non-English Speaking Patients: Patients who are non english speaking will not be accessed to this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: High Dose Ascorbic Acid<br>Subject receives a high dose of infused Vitamin C | Drug: Ascorbic Acid<br>* The infusion of either a high dose of ascorbic acid, low dose ascorbic acid, or placebo<br>* Other names: Vitamin C;|
| Active Comparator: Low Dose Ascorbic Acid<br>Subject receives a low dose of infused Vitamin C | Drug: Ascorbic Acid<br>* The infusion of either a high dose of ascorbic acid, low dose ascorbic acid, or placebo<br>* Other names: Vitamin C;|
| Placebo Comparator: Placebo<br>Subject receives an infusion of saline | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Experienced Ascorbic Acid Infusion Related Arterial Hypotension, Vomiting, or Tachycardia in Septic Patients | There were no instances of arterial hypotension, vomiting, or tachycardia within the study population related to the study drug | during time of infusion- 96 hours from time of enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intensive Care Unit Length of Stay |  | subject will be followed until discharged from the ICU, has deceased, or study duration has reached 28 days from time of enrollment, whichever is first | 
| Duration of Mechanical Ventilation |  | subject will be followed until mechanical ventilation has been discontinued, the subject has deceased, or study duration has reached 28 days from time of enrollment, whichever is first | 
| Ventilator-free Days |  | subject will be followed until discharged from the hospital, has deceased, or study duration has reached 28 days from time of enrollment, whichever is first | 
| Length of Time on Vasopressor Medication |  | during time of infusion - 96 hours from time of enrollment | 
| Multiple Organ Dysfunction Score |  | during time of infusion - 96 hours from time of enrollment | 
| Plasma Cytokine/Chemokine Levels |  | during time of infusions - 96 hours from time of enrollment |