METHODS
After approval of the Research Ethics Committee of Faculty of Pharmacy, Damanhour University (IRB, 1119PP19), protocol registration (NCT04153487, available from https://clinicaltrials.gov/ct2/show/NCT04153487), full written informed consent was taken from each patient’s next of kin to participate and include data in this study. Sample size was calculated using G*Power software (version 3.1.9.4) and setting α error of 0.05, power of 80%, allocation ratio of 1 and effect size of 0.635 for 2-independent means of CRP (two tail t-test). (30)
This double blinded RCT (participant, Care Provider) was carried out on 80 adult (18 – 64 years) critically ill patients diagnosed with TRALI within 6 hours of transfusion at ICU units of two tertiary hospitals between November 2019 and July 2021. Diagnosis of TRALI was defined according to the NHLBI Working Group definitions and or the Canadian Consensus Conference criteria (31, 32) as the following: no evidence of ALI prior to transfusion, onset of ALI ≤ 6 hours following cessation of transfusion, hypoxemia (PaO2/FiO2 ≤ 300 mmHg or SaO2 ≤ 90% on room air), radiographic evidence of bilateral infiltrates, and no prior evidence of left atrial hypertension.
Exclusion criteria were pregnancy, childbearing, breastfeeding, hypernatremia, known hypersensitivity to the study drug, parenteral nutrition containing ascorbic acid, active renal stone or history of urolithiasis, acute Kidney Injury, Glucose-6-phosphate dehydrogenase deficiency, iron or copper storage diseases, and immunocompromised patients (cancer or patients on immunosuppression drugs). Moribund patient not expected to survive 24 hours also were excluded. To avoid prior risk of ARDS, home mechanical ventilation (tracheotomy or noninvasive) was also exclusion except CPAP/BIPAP for sleep-disordered breathing.
All patients were subjected directly to data collection, clinical examination, routine laboratory investigations, chest imaging, and transthoracic echocardiography to confirm the inclusion criteria. In addition to their supportive and standard care, patients were randomly allocated with 1:1 ratio, using computer sheet available from randomizer.org, into 2 groups: ASTRALI (AScorbic acid in TRALI) group (n=40) received 2.5 gm IV ascorbic acid every 6 hrs (using black paper-covered syringe pump and infusion set) for 96 hours from diagnosis (10 gm/day for 4 days) (28, 33). Control group (n=40) received placebo in similar regimen. The used normal saline was calculated with daily fluid chart in both groups. Flow chart of the study according to CONSORT 2010 is illustrated in figure 1.
All patients were followed up and treated during the study time. Glucose monitoring using central laboratory measurements were used during 96 hrs of treatment and 36 hrs later. (34) The primary study outcomes were investigated initially at the day of diagnosis (T0) and after 96 hours (T96). Serum samples were assayed for IL-8, IL-10, IL-1β, SOD, and MDA using commercially available research ELISA kits (IL-8 SunRed no.201-12-0090, IL-10 SunRed no. 201-12-0103, IL-1β SunRed no. 201-12-0144, SOD Cayman no. 706002, MDA FineTest (35)). Total VC levels were directly measured at T0, T48, T96, T120, and T148 using plasma samples. The secondary outcomes were calculated starting from the time of enrollment. Mortality rates were calculated as all-cause mortality. All possible adverse events were monitored such as nausea, vomiting, hypersensitivity, acute kidney injury (AKI), and hyperoxaluria. (36, 37).