Efficacy of Vitamin C on AKI Outcomes in Critically Ill Cirrhotics With Multidrug-resistant Bacterial Infections.
Condition: Liver Cirrhosis
MeSH terms: Bacterial Infections; Liver Cirrhosis
Study type: Interventional

Summary: 
      In this prospective randomized controlled trial we aim to evaluate the impact of vitamin C on
      AKI outcomes in patients with cirrhosis and MDR infections. We also aim to evaluate the
      effects of iv vitamin c on systemic hemodynamics (cardiac output and systemic vascular
      resistive index, extravascular lung water and lung permeability index), endothelial function
      and coagulation, microcirculation (as assessed by lactate clearance and central venous oxygen
      saturation), mitochondrial function, 28-day mortality and vasopressor, ventilator and RRT
      free days in the ICU. The safety and side-effects of vitamin c would also be evaluated.

      Patients with suspected (nosocomial acquisition) or proven MDR infections would be screened
      and randomized to two groups who meet the inclusion and exclusion criteria.

      Group 1: Will receive iv vitamin C (25 mg/kg or max. 1.5 gram every 6 hourly) for maximum 5
      days along with iv antibiotics as per institutional protocol Group 2: iv antibiotics alone
    

Detailed description: 
      Aim & Objectives Primary To evaluate the impact of vitamin C on AKI outcomes in patients with
      cirrhosis and MDR infections

      Secondary Objectives To assess the effects on systemic hemodynamics (cardiac output and
      systemic vascular resistive index, extravascular lung water and lung permeability index)
      Impact of Vitamin C on endothelial function and coagulation Improvement in microcirculation
      as assessed by lactate clearance and central venous oxygen saturation To assess the effects
      on 28-day mortality. Improvement in SOFA scores in both groups Vasopressor, ventilator and
      RRT free days in the ICU Incidence of adverse effects in both groups Prevalence of vitamin C
      deficiency in cirrhotics with sepsis and impact of exogenous vitamin C in improving
      endogenous levels of ascorbate and norepinephrine levels Impact of vitamin C on oxidative
      stress by evaluation of mitochondrial bioenergetics

      (B) Methodology Patients with suspected (nosocomial acquisition) or proven MDR infections
      would be screened and randomized to two groups as under Group 1: Will receive iv vitamin C
      (25 mg/kg or max. 1.5 gram every 6 hourly) for maximum 5 days along with iv antibiotics as
      per institutional protocol Group 2: iv antibiotics alone All patients with nosocomial
      bacterial infections or septic shock would be screened for randomization would be considered
      for enrolment in the trial. Nosocomial infection would be defined as infections developing
      after 48 hours of hospitalization. Following this, patients meeting the inclusion and
      exclusion criteria will be screened and randomized to the two treatment groups. Standard of
      care for management of antibiotics, fluids and vasopressors would be as per institutional
      guidelines. At baseline, blood and urine sample would be stored for all patients for
      performing mitochondrial bioenergetics, endotoxin, proinflammatory cytokines (IL-6, IL-IB,
      TNF-alpha, MCP-1, IL-1O) and urine biomarkers (urine NGAL and cystatin C) and markers of
      endothelial dysfunction(von willebrand factor and ADAMTS). Following randomization patients
      would be allocated to receive intravenous vitamin C (1.5 g every 6 h or 25 mg/kg for 5 days)
      along with intravenous antibiotics

      Study Population:

      Patients with cirrhosis with MDR infections (nosocomial acquisition) or culture-proven

      Study Design:

        -  A randomized controlled study.

        -  The study will be conducted on patients admitted to Department of Hepatology from June
           2020 to December 2020 at ILBS, New Delhi

        -  Study group will comprise of patients critically ill cirrhotics with suspected or proven
           MDR infections

      Study period

        -  The study will be conducted on patients admitted to Department of Hepatology from June
           2020 to December 2020 at ILBS, New Delhi

        -  Study group will comprise of patients critically ill cirrhotics with MDR infections.

      Sample Size calculation: Currently there are lack of studies investigating the incidence and
      outcomes of AKI in this context. The study will be designed as a pilot RCT with an aim to
      enrol 50 patients in each group.

      The detailed cytokine profile, endotoxin assay, markers of endothelial dysfunction and
      bioenergetics would be performed in a subset of 15 patients in each group.

      Intervention: IV Vitamin C

      Monitoring and Assessment: Hourly till the patient is in the intensive care unit then every 7
      days for 1 month

      Statistical analysis

        -  All variables shall be expressed in mean (sd) or median (range)

        -  Variables will be compared by Mann- Whitney U test

        -  For Categorical variables we will use Chi-Square or Fisher's test

        -  Survival analysis will be done using Cox-proportional regression analysis

      Actuarial probability of survival shall be calculated by Kaplan- Meier graph and compared by
      log- rank test.

      Adverse Effects: Any allergic reactions, drop in hemoglobin or development of kidney stones

      Stopping rule of the study: Any untoward adverse effects of the intervention.

      Ethical issues in the study and plans to address these issue The study is designed to
      demonstrate the efficacy of intravenous vitamin C in improving AKI outcomes in cirrhotics
      with MDR infections. Vitamin C is been routinely used in this indication with no major
      adverse effects. However, head-to-head comparison is needed to identify the evidence and
      benefits of using this drug in this indication. Only minor side effects like nausea,
      diarrhea, abdominal bloating, cramps and precipitation of kidney stones have been observed
      with the drug.
    

Intervention name(s): Vit C; Standard medical Treatment
Intervention type(s): Drug; Drug
Intervention description(s): vitamin C (25 mg/kg or max. 1.5 gram every 6 hourly) for maximum 5 day; iv antibiotics alone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment