Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury

Study Overview
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Brief Summary
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Hypothesis 1A: Vitamin C infusion will significantly attenuate sepsis-induced systemic organ failure as measured by Sequential Organ Failure Assessment (SOFA) score, Hypothesis 1B: Vitamin C infusion will attenuate sepsis-induced lung injury as assessed by the oxygenation index and the VE40 Hypothesis 1C: Vitamin C infusion will attenuate biomarkers of inflammation (C-Reactive Protein, Procalcitonin), vascular injury (Thrombomodulin, Angiopoietin-2), alveolar epithelial injury (Receptor for Advanced Glycation Products), while inducing the onset of a fibrinolytic state (Tissue Factor Pathway Inhibitor).

Official Title
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Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury

Conditions
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Acute Lung Injury, Sepsis

Intervention / Treatment
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* Drug: Ascorbic Acid
* Drug: Placebo: 5% Dextrose in water


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have suspected or proven infection, and meet 2 out of 4 of the criteria for Systemic Inflammatory Response (SIRS) due to infection, and be accompanied by at least 1 criterion for sepsis-induced organ dysfunction, and meet all 5 criteria for Acute Respiratory Distress Syndrome (ARDS). Suspected or proven infection: (e.g., thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and central nervous system, see Appendix A). The presence of a systemic inflammatory response: Defined as: fever: >38ºC (any route) or hypothermia: <36ºC (core temp only), tachycardia: heart rate > 90 beats/min or receiving medications that slow heart rate or paced rhythm, leukocytosis: >12,000 WBC/µL or leukopenia: <4,000 WBC/µL or >10% band forms. Respiratory rate > 20 breaths per minute or PaCO2 < 32 or invasive mechanical ventilation. The presence of sepsis associated organ dysfunction: (any of the following thought to be due to infection) Sepsis associated hypotension (systolic blood pressure (SBP) < 90 mm Hg or an SBP decrease > 40 mm Hg unexplained by other causes or use of vasopressors for blood pressure support (epinephrine, norepinephrine, dopamine =/> 5mcg, phenylephrine, vasopressin) Arterial hypoxemia (PaO2/FiO2 < 300) or supplemental O2 > 6LPM. Lactate > upper limits of normal laboratory results Urine output < 0.5 ml/kg/hour for > two hours despite adequate fluid resuscitation Platelet count < 100,000 per mcL Coagulopathy (INR > 1.5) Bilirubin > 2 mg/dL Glasgow Coma Scale < 11 or a positive CAM ICU score ARDS characterized by all the following criteria Lung injury of acute onset, within 1 week of an apparent clinical insult and with progression of respiratory symptoms Bilateral opacities on chest imaging not explained by other pulmonary pathology (e.g. pleural effusions, lung collapse, or nodules) Respiratory failure not explained by heart failure or volume overload Decreased arterial PaO2/FiO2 ratio ≤ 300 mm Hg Minimum PEEP of 5 cmH2O (may be delivered noninvasively with CPAP to diagnose mild ARDS Exclusion Criteria: Known allergy to Vitamin C inability to obtain consent; age < 18 years; No indwelling venous or arterial catheter in patients requiring insulin in a manner that requires glucose being checked more than twice daily (e.g. continuous infusion, sliding scale); presence of diabetic ketoacidosis; more than 48 hrs since meeting ARDS criteria; patient or surrogate or physician not committed to full support (not excluded if patient would receive all supportive care except for cardiac resuscitation); pregnancy or breast feeding, moribund patient not expected to survive 24 hours; home mechanical ventilation (via tracheotomy or noninvasive) except for CPAP/BIPAP used only for sleep-disordered breathing; home O2 > 2LPM, except for with CPAP/BIPAP diffuse alveolar hemorrhage (vasculitis); interstitial lung disease requiring continuous home oxygen therapy; Active kidney stone Non English speaking; Ward of the state (inmate, other)

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: Ascorbic Acid<br>200mg/kg/day divided over 4 doses. Administered every 6 hours for 96 hours | Drug: Ascorbic Acid<br>* Intervention<br>* Other names: Vitamin C;|
| Placebo Comparator: 5% Dextrose in Water<br>50ml every 6 hours for 96 hours | Drug: Placebo: 5% Dextrose in water<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Change in Sequential Organ Failure Assessment (mSOFA) Score | mSOFA is a single score based on patient status of five different biological systems: respiratory, cardiovascular, coagulation, renal, and neurological. Scores range from 0 to 20 with higher scores indicated worse status. | 96 hours | 
| C-Reactive Protein at Study Hours 0, 48, 96, 168 When Compared to Placebo |  | up to 168 hours | 
| Thrombomodulin Protein at Study Hours 0, 48, 96, 168 When Compared to Placebo |  | Up to 168 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygenation Index (FiO2 x Mean Airway Pressure/PaO2) at Study Hour 0, 48, 96, 168 if Still Intubated in Ascorbate Infused Patient Compared to Placebo. |  | Up to hour 168 | 
| VE-40 (Vent RR x TV/Weight) x (PaCO2/40) at Study Hour 0, 48, 96, 168 if Still Intubated, in Ascorbate Infused Patient Compared to Placebo | Estimate of Shunt | Up to hour 168 | 
| mSOFA Scores at Hours 0, 48, 96 | mSOFA is a single score based on patient status of five different biological systems: respiratory, cardiovascular, coagulation, renal, and neurological. Scores range from 0 to 20 with higher scores indicated worse status. | Up to hour 96 | 
| Ascorbate Level at Hour 0, 48, 96, 168 |  | Up to hour 168 | 
| Ventilator Free Days to Day 28 |  | Up to Day 28 | 
| ICU-free Days at Day 28 |  | Up to Day 28 | 
| All Cause Mortality to Day 28 |  | Up to Day 28 | 
| Hospital-free Days at Day 60 |  | Up to Day 60 | 
| Procalcitonin at Study Hour 0, 48, 96, 168 |  | Up to hour 168 | 
| Receptor for Advanced Glycation Endpoints at Study Hour 0, 48, 96, 168 |  | Up to hour 168 | 
| Tissue Factor Pathway Inhibitor at Study Hour 0, 48, 96, 168 |  | Up to hour 168 | 
| Oxygenation Score: Pressure | Oxygenation as measure by the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2). Scores range from 100 to 300 with lower values indicating more worse outcomes | Up to hour 168 | 
| Oxygenation Score: Saturation | Oxygenation as measure by the ratio of arterial oxygen saturation to fraction of inspired oxygen SpO2/FiO2 | Up to hour 168 | 
| Coagulation | Coagulation as measured by Platelets per unit of blood. Scores range from less than 20 to more than 150. Lower scores indicate worse outcomes | Up to hour 168 | 
| Liver Function | Liver function as measured by Total Bilirubin. Normal levels range from 0.2 - 1.2. Levels greater than 1.2 indicate worse outcomes | Up to hour 168 | 
| Cardiovascular Function | Cardiovascular function as measured by Mean arterial pressure. Scores less than 70 mmHg indicate worse outcomes. | Up to hour 168 | 
| State of Consciousness | State of consciousness as measure by Glasgow Coma Scale which gives a score based on eye, verbal, and motor responses. Scores range from 3 to 15 with lower scores indicating worse outcome | Up to hour 168 | 
| Renal Function | Renal function as measured by Creatinine. Scores range from less than 1.2 to greater than 5.0 with higher scores indicating worse outcomes | Up to hour 168 |