Clinical trial NCT04153487: Role of Ascorbic Acid Infusion in Critically Ill Patients With Transfusion Related Acute Lung Injury
Official title: Role of Ascorbic Acid Infusion in Critically Ill Patients With Transfusion Related Acute Lung Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Lung Injury, Transfusion Related
Keywords: Transfusion Reaction
Transfusion Related Complication
Acute Lung Injury
Critical Care
Lead sponsor: Damanhour University
Sponsor class: OTHER
Collaborators: name: Alexandria University
First posted: 2019-11-06
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized Controlled Trial
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Adult (18 - 64 years) critically ill patients diagnosed with transfusion related acute lung injury (TRALI), at the time of enrollment or maximum 6 hours before, according to the National Heart, Lung and Blood Institute (NHLBI) Working Group definitions and or the Canadian Consensus Conference criteria (29, 30) as the following criteria;

  * No evidence of ALI prior to transfusion.
  * Onset of ALI ≤ 6 hours following cessation of transfusion.
  * Hypoxemia, defined as the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) ≤ 300 mmHg or oxygen saturation ≤ 90% on room air.
  * Radiographic evidence of bilateral infiltrates.
  * No evidence of left atrial hypertension.

Exclusion Criteria:

* Pregnancy or breastfeeding.
* Hypernatremia or known hypersensitivity to the study drug.
* Parenteral nutrition (total/partial) containing vitamin C.
* Active renal stone or history of urolithiasis.
* Acute Kidney Injury.
* Glucose 6 phosphate dehydrogenase deficiency, iron and copper storage diseases.
* Immunocompromised patients (cancer or patients on immunosuppressive drugs).
* Moribund patient not expected to survive 24 hours .
* Home mechanical ventilation (via tracheotomy or noninvasive) except for Continuous Positive Airway Pressure/ Bilevel Positive Airway Pressure (CPAP/BIPAP) used only for sleep-disordered breathing .

Primary outcomes:
measure: Interleukin-8 (IL-8)
timeFrame: 96 hrs
measure: Interleukin-10 (IL-10)
timeFrame: 96 hrs
measure: C-reactive protein (CRP)
timeFrame: 96 hrs
measure: Superoxide Dismutase (SOD)
timeFrame: 96 hrs
measure: Malondialdehyde (MDA)
timeFrame: 96 hrs
Secondary outcomes:
measure: Vasopressor use (days)
timeFrame: up to 28 days
measure: Duration of Mechanical Ventilation (days)
timeFrame: up to 28 days
measure: ICU length of stay (days)
timeFrame: Up to 28 days
measure: 7-days Mortality
timeFrame: 7 days
measure: 28-days Mortality
timeFrame: 28 days
Other outcomes:
Locations:
city: Beheira
country: Egypt
facility: Damanhour University
Study officials:
affiliation: Professor of Biochemistry, Damanhour University.
name: Gamal A Omran, PHD
role: STUDY_DIRECTOR
affiliation: Professor of Critical Care Medicine, Alexandria University.
name: Mohamed M Megahed, MD
role: STUDY_DIRECTOR
affiliation: Ass. Professor of Critical Care Medicine, Alexandria University.
name: Tamer N Zakhary, MD
role: STUDY_CHAIR
affiliation: Lecturer of Clinical Pharmacy, Damanhour University.
name: Amira B Kassem, PHD
role: STUDY_CHAIR
affiliation: Clinical Pharmacy Specialist, Damanhour University.
name: Islam E Ahmed, PharmD
role: PRINCIPAL_INVESTIGATOR
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