Sepsis
Conditions
Brief summary
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.
Interventions
DRUGAscorbic Acid
OTHERNormal Saline
Sponsors
Christiana Care Health Services
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Modified SOFA Score | Baseline and 72 hours | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ascorbic Acid Concentration at 32 Hours | 32 Hours | Ascorbic Acid Concentration Normal Ascorbic Acid Range 0.4-2.0 mg/dL |
| ICU Length of Stay | Length of ICU stay up to 200 hours | ICU Length of Stay in Hours |
| Modified SOFA Score | at 72 Hours | 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. |
| Change in PIRO Score | Baseline and 72 hours | 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. |
| Percentage of Participants Who Died | From initial hospital admission through discharge, up to 2 weeks. | — |
| Hospital Length of Stay | From ICU admission through ICU discharge, up to 2 weeks | From admission until discharge from ICU in days |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Ascorbic Acid | 12 |
| Placebo The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours.
Normal Saline | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | High Dose IV Ascorbic Acid | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 7 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 5 Participants | 11 Participants |
| Age, Continuous | 67.6 years STANDARD_DEVIATION 13.6 | 70.2 years STANDARD_DEVIATION 14.4 | 68.9 years STANDARD_DEVIATION 13.8 |
| Ascorbic Acid Concentration, Baseline | 0.3 mg/dL STANDARD_DEVIATION 0.3 | 0.4 mg/dL STANDARD_DEVIATION 0.3 | 0.3 mg/dL STANDARD_DEVIATION 0.3 |
| Ascorbic Acid Concentrations <0.4 mg/dL, Baseline | 72.7 percentage of participants | 36.6 percentage of participants | 68.1 percentage of participants |
| ICU Admission | 5 Participants | 5 Participants | 10 Participants |
| Modified SOFA Score, Baseline | 5.2 units on a scale STANDARD_DEVIATION 2.5 | 5.0 units on a scale STANDARD_DEVIATION 2.3 | 5.1 units on a scale STANDARD_DEVIATION 2.3 |
| PIRO Score, Baseline | 15.4 scores on a scale STANDARD_DEVIATION 3.9 | 15.9 scores on a scale STANDARD_DEVIATION 4 | 15.7 scores on a scale STANDARD_DEVIATION 3.9 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment United States | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 7 Participants | 9 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 12 | 2 / 12 |
| other Total, other adverse events | 6 / 12 | 4 / 12 |
| serious Total, serious adverse events | 2 / 12 | 2 / 12 |
Outcome results
Primary
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.
Time frame: Baseline and 72 hours
Population: Data was not available for 3 participants in the treatment group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose IV Ascorbic Acid | Change in Modified SOFA Score | -1.0 units on a scale | Standard Deviation 4.4 |
| Placebo | Change in Modified SOFA Score | -1.75 units on a scale | Standard Deviation 3 |
p-value: 0.631Other
Secondary
Ascorbic Acid Concentration at 32 Hours
Ascorbic Acid Concentration Normal Ascorbic Acid Range 0.4-2.0 mg/dL
Time frame: 32 Hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose IV Ascorbic Acid | Ascorbic Acid Concentration at 32 Hours | 13.8 mg/dL | Standard Deviation 10.9 |
| Placebo | Ascorbic Acid Concentration at 32 Hours | 0.22 mg/dL | Standard Deviation 0.21 |
p-value: 0.006Fisher Exact
Secondary
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.
Time frame: Baseline and 72 hours
Population: Data was not available for 3 participants in the treatment group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose IV Ascorbic Acid | Change in PIRO Score | -3.7 units on a scale | Standard Deviation 3 |
| Placebo | Change in PIRO Score | -4.5 units on a scale | Standard Deviation 3.9 |
p-value: 0.566Other
Secondary
Hospital Length of Stay
From admission until discharge from ICU in days
Time frame: From ICU admission through ICU discharge, up to 2 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High Dose IV Ascorbic Acid | Hospital Length of Stay | 7 Days |
| Placebo | Hospital Length of Stay | 6 Days |
p-value: 0.133Fisher Exact
Secondary
ICU Length of Stay
ICU Length of Stay in Hours
Time frame: Length of ICU stay up to 200 hours
Population: Data was not available for 7 participants in both groups.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High Dose IV Ascorbic Acid | ICU Length of Stay | 29 Hours |
| Placebo | ICU Length of Stay | 47 Hours |
p-value: 0.655Fisher Exact
Secondary
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.
Time frame: at 72 Hours
Population: Data was not available for 3 participants in the treatment group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose IV Ascorbic Acid | Modified SOFA Score | 4.1 units on a scale | Standard Deviation 4.8 |
| Placebo | Modified SOFA Score | 3.3 units on a scale | Standard Deviation 3.7 |
p-value: 0.64Other
Secondary
Percentage of Participants Who Died
Time frame: From initial hospital admission through discharge, up to 2 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose IV Ascorbic Acid | Percentage of Participants Who Died | 16.7 Percentage of participants |
| Placebo | Percentage of Participants Who Died | 16.7 Percentage of participants |
p-value: 1Chi-squared