Clinical trial NCT02106975: Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury
Official title: Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Lung Injury
Sepsis
Lead sponsor: Virginia Commonwealth University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2014-04-08
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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)

Primary outcomes:
measure: Modified Change in Sequential Organ Failure Assessment (mSOFA) Score
timeFrame: 96 hours
measure: C-Reactive Protein at Study Hours 0, 48, 96, 168 When Compared to Placebo
timeFrame: up to 168 hours
measure: Thrombomodulin Protein at Study Hours 0, 48, 96, 168 When Compared to Placebo
timeFrame: Up to 168 hours
Secondary outcomes:
measure: 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.
timeFrame: Up to hour 168
measure: 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
timeFrame: Up to hour 168
measure: mSOFA Scores at Hours 0, 48, 96
timeFrame: Up to hour 96
measure: Ascorbate Level at Hour 0, 48, 96, 168
timeFrame: Up to hour 168
measure: Ventilator Free Days to Day 28
timeFrame: Up to Day 28
measure: ICU-free Days at Day 28
timeFrame: Up to Day 28
measure: All Cause Mortality to Day 28
timeFrame: Up to Day 28
measure: Hospital-free Days at Day 60
timeFrame: Up to Day 60
measure: Procalcitonin at Study Hour 0, 48, 96, 168
timeFrame: Up to hour 168
measure: Receptor for Advanced Glycation Endpoints at Study Hour 0, 48, 96, 168
timeFrame: Up to hour 168
measure: Tissue Factor Pathway Inhibitor at Study Hour 0, 48, 96, 168
timeFrame: Up to hour 168
measure: Oxygenation Score: Pressure
timeFrame: Up to hour 168
measure: Oxygenation Score: Saturation
timeFrame: Up to hour 168
measure: Coagulation
timeFrame: Up to hour 168
measure: Liver Function
timeFrame: Up to hour 168
measure: Cardiovascular Function
timeFrame: Up to hour 168
measure: State of Consciousness
timeFrame: Up to hour 168
measure: Renal Function
timeFrame: Up to hour 168
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University and Grady Memorial Hospital
state: Georgia
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Cleveland
country: United States
facility: The Cleveland Clinic
state: Ohio
city: Richmond
country: United States
facility: Virginia Commonwealth University Health System
state: Virginia
city: Milwaukee
country: United States
facility: Froedtert and The Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Virginia Commonwealth University
name: Alpha B. Fowler, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, Fisher B, Thacker LR 2nd, Natarajan R, Brophy DF, Sculthorpe R, Nanchal R, Syed A, Sturgill J, Martin GS, Sevransky J, Kashiouris M, Hamman S, Egan KF, Hastings A, Spencer W, Tench S, Mehkri O, Bindas J, Duggal A, Graf J, Zellner S, Yanny L, McPolin C, Hollrith T, Kramer D, Ojielo C, Damm T, Cassity E, Wieliczko A, Halquist M. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019 Oct 1;322(13):1261-1270. doi: 10.1001/jama.2019.11825.