After obtaining ethics committee approval and getting informed consent from patients or their legal guardian (When the level of consciousness of patients was low), 80 critically ill patients with pneumonia were enrolled in this randomized double blinded clinical trial. (Trial registration number: IRCT, 20190312043030N1). All patients who were admitted to intensive care unit (ICU) of a university-affiliated hospital in northwest of Iran with the diagnosis of severe pneumonia were enrolled in this study from May 2019 till Dec 2019. We defined nosocomial pneumonia as the pneumonia in patients admitted to the hospital for >48 h. Among nosocomial pneumonias, ventilator-associated pneumonia (VAP) develops in intensive care unit (ICU) patients who have been mechanically ventilated for at least 48 h. Patients with severe nosocomial pneumonia who require mechanical ventilation during their treatment after the onset of infection do not met the definition of VAP13. Patients with CURB-65 score >3, one major criteria, or ≥3 minor criteria were considered as severe pneumonia. Exclusion criteria were age less than 18 and more than 80 years old, renal insufficiency, history of vitamin C usage during past 48 hours, allergy to vitamin C, pregnancy or breastfeeding, life expectancy of less than 24 hours; previously complicated with end-stage lung disease, end-stage malignancy, glucose-6-phosphate dehydrogenase deficiency, diabetic ketoacidosis, active kidney stone disease, and participation in another clinical trial at the same time and immunocompromised patients. Severity of pneumonia was diagnosed based on CURB-65 (confusion, uremia, respiratory rate, BP, and age ≥ 65 years) and PSI index. We will construct 6 blocks in AABB, BBAA, ABAB, BABA, ABBA and BAAB using four blocks. We will assign 1 to 6 for each block. Then, using the random number table, based on the sample size, 20 units of 4 blocks will be selected so that we consider having 40 people in control group (A) and 40 people in intervention group (B). Therefore, we will do block randomization. In this study, patients, clinical caregivers, and data analyzers will not aware of grouping.
Patients were randomly assigned to one of the following groups: intervention group in which patients received standard treatment plus 60 mg/kg/day vitamin C as continuous infusion for 96 hours. Patients in control group received standard treatment plus intravenous infusion of normal saline as the placebo in the same volume. Standard pneumonia therapy included of empirical antibiotic therapy before the administration of appropriate antibiotic based on the bacteria isolated on laboratory testing, as well as adjunct respiratory therapy. The types of antibiotics were started empirically for coverage of possible gram negative, gram positive and anerobes with simultaneously performing cultures for source identification. Mostly our used antibiotics for empirical therapy were carbapnemes/piperacilline tazobactam plus a fluroquinolone with or without vancomycine/linezolide. After obtaining the results antibiotics were changed as targeted therapy based on culture and microbiological results.
Patients' demographic characteristics were recorded during the study period. Sequential organ failure assessment (SOFA) was assessed during the study and acute physiologic and chronic health evaluation (APACHEII) was assess on the first day of ICU admission. We evaluated patients for any complication during intravenous infusion of vitamin C including hypotension (systolic blood pressure less than 70 mmHg or 30% decrease compared to the baseline), tachycardia (increase more than 20% compared to baseline or heart rate more than 120/min), nausea/vomiting and hypernatremia. If any of the aforesaid complications was seen, the rate of administration of vitamin C was decreased by 50% and if it continued, the infusion was stopped. Serum level of vitamin C were noted at baseline and 48 hours after vitamin C administration. Duration of mechanical ventilation, ICU length of stay, PaO2/FiO2 and mortality rate were noted for all patients until the 28th day.
Sample size was calculated based on the α-error of 5% and power of 80% as 36 subjects per group which was increased to 40 in each group. Data were analyzed using SPSS 17 software and reported as mean ± standard deviation for the continuous variables, and percentage for discrete variables. Non continuous variables were analyzed with Chi-square and continuous variables were analyzed with T-test. Organ dysfunction indices based on SOFA/APACHE scores were compared by regression correlation and T-test. A P-value of less than 0.05 was considered significant.