Role of Ascorbic Acid Infusion in Critically Ill Patients With Transfusion Related Acute Lung Injury
Condition: Acute Lung Injury, Transfusion Related
MeSH terms: Lung Injury; Acute Lung Injury; Transfusion-Related Acute Lung Injury; Wounds and Injuries
Study type: Interventional
Phase: Phase 2

Summary: 
      TRALI was defined as "acute noncardiogenic pulmonary edema typically occurs ≤ 6 hours
      following transfusion of plasma-containing blood products, such as packed red blood cells,
      fresh frozen plasma, platelets, or cryoprecipitate." In critically ill patients, TRALI
      remains the leading cause of transfusion-related fatalities and is accompanied by a very
      significant morbidity and mortality. Survival in such patients is as low as 53% compared with
      83% in acute lung injury (ALI) controls.

      The incidence of TRALi is likely underreported. In densely populated developing countries,
      incidence has not decreased due to lack of male-only strategy for plasma donation.

      TRALI is associated with systemic inflammation characterized by low anti-inflammatory
      cytokine as interleukin (IL)-10, increased pro-inflammatory cytokine as IL-8. Regulation of
      inflammation should include avoidance of overproduction of inflammatory mediators. So, it can
      be dampened not only by increasing IL-10 but also by decreasing IL-1β release. C-reactive
      protein (CRP) is an acute phase protein which is up-regulated during infections and
      inflammation. CRP was recently identified as a novel first hit in TRALI.

      Till now, there is no established treatment for TRALI beyond supportive care and monitoring.
      Recently, potential therapies have been reviewed, and it was concluded that the most
      promising therapeutic strategies are IL-10 therapy, downregulation of CRP levels, targeting
      reactive oxygen species (ROS) or blocking IL-8 receptors. So, antioxidants (such as high dose
      vitamins), were recommended for future studies as potentially effective treatment.

      Vitamin C hypovitaminosis is observed in 70% of critically ill despite receiving recommended
      daily doses.

      The aim of this study is to investigate the role of intravenous vitamin C (ascorbic acid) as
      a targeted therapy for transfusion related acute lung injury (TRALI) in critically ill
      patients in terms of IL-8, IL-10, CRP, SOD, malondialdehyde (MDA), vasopressor use, duration
      of mechanical ventilation, ICU length of stay, 7-days mortality and 28-days mortality.
    

Detailed description: 
      1. Ethical committee approval will be obtained from Ethics committee of Faculty of
           Pharmacy, Damanhour University.

        2. The minimum required sample size is estimated to be 40 patients for each group.

        3. Full written informed consent will be taken from all patients or their next of kin to
           participate in this study.

        4. All patients will be subjected directly at time of enrollment to the following;

             -  Complete history taking and demographic data

             -  The potential recipient risk factors for TRALI.

             -  The initial cause of ICU admission and the blood products received.

             -  Complete physical examination including chest auscultations.

             -  Vital signs

             -  Routine laboratory investigations

             -  Brain natriuretic peptide level

             -  Troponin T

             -  Hypoxic index

             -  Acute Physiology and Chronic Health Evaluation version II (APACHE II) score.

             -  Sequential Organ Failure Assessment (SOFA) score.

             -  Kidney Disease Improving Global Outcomes (KDIGO) criteria.

             -  Child Pugh score.

             -  Chest radiography and transthoracic echocardiography.

        5. Samples will be drawn to measure the initial values of ascorbate level, plasma IL-8,
           IL-10, IL-1β, SOD, MDA and serum CRP.

        6. Eighty patients with confirmed TRALI (n=80) will be enrolled from critical care units
           (tertiary hospitals). Then, in addition to their supportive and standard care, they will
           be randomized (computer sheet) into two groups:

             -  ASTRALI (AScorbic acid in TRALI) group (n=40) will receive 2.5 gm vitamin C
                intravenously every 6 hrs for 96 hrs from diagnosis.

             -  Control group (n=40) will receive placebo in similar regimen.

        7. All patients will be followed up and treated during the study time. All relevant routine
           investigations, supportive measures, medications and ventilatory data will be recorded.

        8. All possible adverse events will be monitored, recorded and managed directly.
           Hyperoxaluria, microscopic calcium-oxalate crystallization or oxalate nephropathy will
           be monitored, recorded and managed directly.

        9. After 96 hrs, resampling for ascorbate level and the same biomarkers will be done.

       10. Measuring the study secondary outcomes will include vasopressor use, duration of
           mechanical ventilation, ICU length of stay, 7-days mortality and 28-days mortality.

       11. Statistical tests appropriate to the study design will be conducted to evaluate the
           significance of the results.
    

Intervention name(s): Ascorbic Acid Injectable Product; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Intermittent Intravenous Infusion of Ascorbic Acid (Vitamin C) 2.5 gm / 6 hours for 96 hours; Placebo saline / 6 hours for 96 hours
Other intervention name(s): Vitamin C; Normal saline
Intervention MeSH terms: Ascorbic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized Controlled Trial
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Transfusion Reaction; Transfusion Related Complication; Acute Lung Injury; Critical Care