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).