Clinical randomized trial of vitamin D and C supplementation in critically ill patients with respiratory failure

Clinical randomized trial of vitamin D and C supplementation in critically ill patients with respiratory failure | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical randomized trial of vitamin D and C supplementation in critically ill patients with respiratory failure Aynaz velayati, Mohammadreza vafa, Mahdi Yadollahzadeh, Zahra Vahdat Shariatpanahi, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6683114/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Sep, 2025 Read the published version in Nutrition Journal → Version 1 posted 9 You are reading this latest preprint version Abstract Background Acute respiratory failure (ARF) is the most common organ failure, affecting up to 30% of all intensive care unit (ICU) admissions. Since vitamin deficiencies are frequent in critically ill patients, and considering that the two primary mechanisms involved in ARF are inflammation and oxidative stress, this study aims to investigate the effects of co-supplementation of vitamins D and C on inflammatory parameters, oxidative stress, and clinical outcomes in critically ill ARF patients. Methods In this double-blind, randomized, placebo-controlled trial, ARF patients admitted to the ICU were randomly assigned to either the intervention group (daily 2000 mg of intravenous vitamin C plus 5000 IU of oral vitamin D) or the control group (placebo). The intervention lasted 10 days, and patients were followed for 90 days, assessing inflammation, oxidative stress parameters, and clinical outcomes. Results Thirty-four patients in the intervention group and 33 in the control group completed the trial. At the end of the intervention, High-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and malondialdehyde (MDA) were significantly reduced, while total antioxidant capacity (TAC) increased significantly in the intervention group compared to both the baseline and the control group (p < 0.001). Among the clinical outcomes, only the duration of ICU stay was shorter in the intervention group (0.028). However, 90-day survival (HR 0.55; 95% CI 0.21–1.41; P = 0.22) did not show a significant difference between the two groups. Conclusions Our study concluded that vitamin D and C supplementation may improve inflammation and oxidative status in critically ill ARF patients, reducing ICU stays but not affecting 90-day mortality. Trial registration The study has been registered at https://irct.behdasht.gov.ir/ . Number: IRCT20090822002365N29.Registered on 2023-08-05 and it was ethically approved by the Committee of Iran University of Medical Sciences (registration IR.IUMS.REC.1402.210). Acute respiratory failure Vitamin C Vitamin D Inflammation Oxidative stress Figures Figure 1 Introduction Acute respiratory failure (ARF) is a critical organ dysfunction characterized by hypoxia, which can occur with or without hypercapnia. [ 1 – 3 ]. It is a leading cause of admissions to intensive care units (ICUs), accounting for approximately 30% of all ICU admissions[ 4 – 8 ]. ARF is associated with significant use of medical resources, increased demands on healthcare staff, longer durations of mechanical ventilation, extended stays in both the ICU and the hospital, and a high mortality rate that exceeds 40%[ 5 , 6 ]. While mechanical ventilation (MV), whether invasive (IMV) or non-invasive (NIV), can provide vital support and time to treat underlying causes of ARF (1,7), it can also lead to complications such as ventilator-induced lung injury and oxygen toxicity[ 9 , 10 ]. These complications may trigger inflammatory responses, activate cytokines, and recruit other inflammatory mediators, producing reactive oxygen species (ROS) [ 11 ]. In response to hypoxia in ARF, cells increasingly depend on anaerobic respiration, which leads to heightened glycolysis and lactic acid accumulation. This metabolic shift activates pathways that promote the formation of ROS and pro-inflammatory mediators. In summary, inflammation and oxidative stress—driven by underlying health issues, tissue hypoxemia, and mechanical ventilation—play a crucial role in the development of ARF and contribute to its adverse outcomes [ 12 , 13 ]. On the other hand, vitamin deficiencies, especially vitamin D (Over 80%) and vitamin C (up to 30%), are common in critically ill patients due to reduced intake and increased requirements[ 14 – 20 ], which worsens the inflammation situation, oxidative conditions and clinical outcomes, including duration of MV, ICU, and hospital stay, and mortality rate due to their anti-inflammatory and antioxidant roles[ 14 – 24 ]. Despite the limited evidence concerning vitamin levels in ARF patients admitted to ICU, prior research has demonstrated that critically ill patients suffering from ARF due to Coronavirus disease 19 (COVID-19) display a distinctly elevated prevalence of vitamin D deficiency [ 25 ]. Specifically, those with preadmission serum vitamin D levels below 30 ng/ml are at an elevated risk of developing ARF compared to individuals with sufficient vitamin D levels[ 26 ]. Recent studies have indicated that vitamin D supplementation could play a critical role in decreasing in-hospital and ICU mortality rates for patients with ARF who are admitted to the ICU [ 27 ]. Previous researches evaluated the impact of these vitamins in critically ill patients, which has yielded conflicting findings. Despite the high prevalence of ARF in the ICU and widespread deficiencies of vitamins D and C in these patients, no study has specifically assessed the effects of these vitamins on ARF patients. Therefore, this article aims to examine the effects of simultaneous oral vitamin D and intravenous vitamin C supplementation on inflammatory markers, oxidative stress, and clinical outcomes in patients with respiratory failure in the intensive care unit. Methods and materials Study design and ethics patients The double-blind randomized placebo-controlled trial was conducted over one year (November 2023-Novamber 2024), involving patients over 18 and under 75 years old admitted to the ICU of Firoozgar Hospital in Tehran, Iran. Ethics The study protocol was registered at https://irct.behdasht.gov.ir/ (No: IRCT20090822002365N29), and it was ethically approved by the Committee of Iran University of Medical Sciences (registration IR.IUMS.REC.1402.210). The study was developed and conducted in accordance with the Declaration of Helsinki and was reported based on the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Subjects and eligibility criteria ARF Patients eligible for this study must have been admitted to the ICU within 24 hours and consented to participate. They should not have a history of nervous system disease that prevents discharge from mechanical ventilation, hypercalcemia (total calcium > 10.6 mg/dL), hyperphosphatemia (> 1.45 mmol/L), sarcoidosis, tuberculosis, AIDS, liver or renal failure, and gout. Additionally, they should not have participated in other randomized clinical trials before or after ICU admission, be pregnant or breastfeeding, or have consumed vitamin D or vitamin C in the 30 days before ICU admission. Exclusion criteria were death or discharge from the ICU sooner than 3 days, request for stop intervention or unwillingness to continue studying, and developing contraindications for administering vitamin D and vitamin C based on the attending physician's opinion at the time of the study. Randomization and blinding A total of 82 consecutive patients were evaluated for eligibility. Patients were excluded after the initial assessment due to mortality within 3 days in the ICU, discharge from this unit in less than 3 days, or lack of willingness to continue. As a result, eligible patients were randomly assigned to either the intervention or control groups at a 1:1 ratio using the block randomization technique. A blinded randomization list of quadruple blocks will be generated through a web-based system for clinical trials (www.sealedenvelope.com ). This study is structured as a double-blind study, meaning that throughout the duration of the research, the participants, researchers, healthcare personnel, and the statistician will be unaware of the group allocation. To ensure effective blinding, the drug (consisting of a vitamin D supplement and serum containing vitamin C) and the placebo (comprising miglyol and serum without vitamin C) were designed to be indistinguishable in terms of smell, color, and packaging. The only individual informed about the treatment was the nurse overseeing the study intervention. Intervention and Adherence The intervention lasted between 3 and 10 days, depending on the duration of the patient's ICU stay. Patients in the intervention group were administered five mL of vitamin D drops (containing 5000 IU of 25-hydroxyvitamin D) via oral intake or enteral formula and two thousand mg of vitamin C via continuous infusion or normal saline that was prepared and administrated for patients by a trained pharmacist who did not engage in any part of the study. Conversely, during this period, the control group received a placebo (containing Miglyol) instead of vitamin D drops and an infusion without vitamin C. Vitamin D was given in enteral formula through a feeding tube for patients receiving enteral feeding. Safety evaluations To ensure compliance, tolerability and potential adverse effects, the main investigator (A.V) reviewed the nurse's records daily. Study endpoints The primary outcome of the study was the change in serum interleukin-6 (IL-6), an inflammation marker. Secondary outcomes included changes in serum C-reactive protein (CRP), total antioxidant capacity (TAC), malondialdehyde (MDA), and clinical outcomes such as 90-day mortality and days free from hospitalization, ICU admission, and mechanical ventilation. Assessment of clinical, respiratory, and anthropometric parameters In this clinical trial, eligible patients were enrolled after obtaining written informed consent from either the patient or their relatives. Following this, a comprehensive profile sheet capturing demographic information, including age, sex, comorbidities (such as hypertension, diabetes, dyslipidemia), the underlying cause of respiratory failure, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, was completed for each patient. Arterial blood gases and mechanical ventilation respiratory parameters were recorded for each patient. Daily assessments were performed for each patient to evaluate organ failures, including cardiovascular, central nervous system, coagulation, hepatic, and renal failures. Following their discharge from the ICU, patients underwent a 90-day monitoring period to assess rehospitalization and mortality rates without any additional intervention. The 25(OH)D level was measured at the beginning and end of the intervention using high-performance liquid chromatography (HPLC) to show any changes. Vitamin D deficiency is defined as a 25(OH)D level lower than 20 ng/mL, insufficiency ranging from 21 to 30 ng/mL, and sufficiency at levels higher than 30 ng/mL. The Nutrition Risk in Critically Ill (NUTRIC) score was calculated at the start and end of the trial using relevant questionnaires. The Sequential Organ Failure Assessment (SOFA) score was measured every day by ICU nurses. If available, the patients' height and weight were recorded from their medical records, otherwise recumbent height assessed by using a flexible tape with an accuracy of 0.5 cm and weight were calculate through ideal body weight (IBW). Nutritional parameters including routes of nutrition intake (oral or enteral) and energy and protein intake percentages were recorded for each patient daily. Measurement of blood biochemical parameters A trained healthcare professional collected a 5-milliliter blood sample from a vein in the arm using a vacutainer tube before and after the intervention. The sample was promptly chilled and transported to the laboratory for processing. Upon arrival, it was centrifuged at 3000 revolutions per minute at 4 degrees Celsius for 10 minutes to separate the serum, which was then stored at -80 degrees Celsius until it was ready for biochemical analysis. Inflammatory markers such as IL-6 and hs-CRP were quantified using enzyme-linked immunosorbent assay (ELISA) and specific ELISA kits for cytokines. Additionally, ELISA kits were used to measure MDA levels in the serum, while spectrophotometric methods were employed to assess TAC levels as an oxidative marker. Data management Each patient was assigned a unique ID and assured that their data would remain confidential. All information, including questionnaires, records, and laboratory results, was coded by a data management team and entered into IBM SPSS Statistics v 27.0 software. The coded data was subsequently provided to a study statistician for analysis. Sample size The sample size for this Randomized Controlled Trial (RCT) comparing IL-6 as the primary outcome between the intervention and control groups was determined using Stata 17 software. We employed a two-way comparison formula and referred to a previous study[ 28 ], considering an effect size corresponding to a 40% reduction in IL-6, 80% power, and a 0.05 alpha error. This calculation indicated that 32 participants were needed for each group. Allowing for a 10% dropout rate, our target is to recruit 70 patients (35 patients per group). Statistical analysis The intention-to-treat principles used for main analyses. The normality of these variables was evaluated using the Kolmogorov‒Smirnov test. Continuous variables were presented as Mean ± Standard Deviation (SD) or median (interquartile range) as appropriate. Independent t-tests or the Mann‒Whitney U test will be used to compare normally or non-normally distributed indicators, respectively, between the two groups. Nominal variables were shown as frequencies (%) and analyzed using the chi-square test. To assess the duration of patients' stay in the ICU and hospital and their need for mechanical ventilation, we calculated the number of ICU and hospital-free days (IFD and HFD) and mechanical ventilation-free days(MFD) in 28 days after ICU admission. The 28-day and 90-day mortality rates were compared between the two groups using survival analysis and a Cox regression model, with the time of death recorded. The significance level for the tests is 0.05, and all analyses were conducted using IBM SPSS Statistics v 27.0 software. There are no planned subgroup analyses or interim analyses for this trial. Results Demographic and nutritional characteristics As per the exclusion criteria, a total of 3 out of 70 patients were excluded from the study. Of these included patients, two patients were excluded because of discharge and death before 3 days of admission in the ICU, and one patient was due to unwillingness to continue studying. As a result, the study was completed by 67 patients, including 24 males in the control group and 19 males in the intervention group, which is not statistically significant (Fig. 1). The general characteristics, comorbidities, severity of illness, baseline laboratory parameters, and nutritional variables of patients are presented in Table 2. There were no significant differences in the prevalence of comorbidities, the APACHE II and SOFA scores, laboratory and respiratory parameters and nutritional indices, such as nutritional routes and energy and protein intake, between the intervention and the control groups (P > 0.05). Table1. Demographic and nutritional characteristics of patients according to randomly assigned treatment group Variables Control group (n= 33 ) Intervention group (n= 34 ) P-value General characteristics Age (Mean± SD) 66.76±9.96 66.12±8.15 0.77 a Gender Male, n (%) 19(57.5) 24(70.6) 0.26 b Smoking status (yes)n% 12(36.3) 10(29.4) 0.54 b Addiction, n(%) 7(21.2) 9(26.4) 0.61 b Underlying disease n (%) COPD 11(33.3) 11(32.4) 0.28 b pneumonia 8(24.2) 11(32.4) Pleural effusion 8(24.2) 2(5.9) ARDS 3(9.1) 5(14.7) Others 3(9.1) 5(14.7) Comorbidities n (%) Respiratory disease, n(%) 32(96.9) 31(91.1) 0.31 b Hypertension, n(%) 19(57.6) 19(55.9) 0.88 b Diabetes, n(%) 9(27.3) 9(26.4) 0.94 b Dyslipidemia, n(%) 16(48.5) 12(35.3) 0.27 b Severity of illness APACHE II score 16(14-22) 17(14-23) 0.49 c SOFA score admission 3(2-11) 5.5(2.75-10) 0.29 c Nutric score 5(4-7) 5(5-7) 0.17 c Laboratory parameters Admission Blood glucose (mg/dL) (Mean± SD) 172.45±62.55 145.29±91.38 0.18 a Creatinine mg/dl 1.14±0.42 1.34±0.57 0.11 a WBC count, 10 9 /L 9.88±3.80 9.82±4.1 0.95 a RBC 4.46±0.85 425±0.81 0.33 a Hemoglobin, g/dl 12.20±1.97 12.21±2.56 0.99 a Admission Albumin (g/dL) 3.09±0.45 3.00±0.55 0.58 a Plasma 25OHD (ng/mL) 24.52±14.47 21.06±12.76 0.38 a Deficiency n(%) 14(42.4) 18(52.9) 0. 25 b Insufficiency n(%) 9(27.3) 7(20.6) Sufficient n(%) 9(27.3) 8(23.5) Respiratory parameters Type of ventilation Venturi mask, n(%) Bipap, n(%) Ventilator, n(%) 4(12.1) 19(5736) 10(30.3) 6(17.6) 19(55.9) 9(26.5) 0.80 b Nutritional parameters Nutritional routs Oral, n(%) Enteral, n(%) 23(69.7) 10(30.3) 24(70.6) 10(29.4) 0.93 b Mean energy intake (kcal/day) 1448.86±188.78 1540.75±202.68 0.059 a Mean protein intake(gr/day) 45.04±6.83 47.26±6.73 0.18 a a Independent Samples T Test; b Chi-square test, n (%); c Mann-Witheny U Abbreviations: ARDS: Acute Respiratory Distress Syndrome; APACHI II score: Acute Physiology and Chronic Health Evaluation II; COPD: Chronic Obstructive Pulmonary Disease; NUTRIC score: Nutrition Risk in Critically Ill; SOFA score: Organ Failure Assessment Biomarkers of oxidative stress and inflammation Table 2 presents the baseline levels and changes in vitamin D, oxidative stress, and inflammation biomarkers. There were no significant differences in serum vitamin D, oxidative stress, and inflammation parameters levels between the two groups at the baseline (P > 0.05). Serum vitamin D levels decreased significantly in the control group during their ICU stay (changes=-1.95±4.51 p=0.01). At the same time, they increased in the intervention group (changes=2.04±2.57 P30 ng/ml) and the mean level of vitamin D is not statistically significant between the two groups(P=0.74). After 10 days of intervention, the mean serum levels of IL-6 and hs-CRP were significantly reduced in intervention groups (P<0.001), while inversely, these increased in the control group compared with the baseline. On the 10th day of the study, the serum level of TAC significantly increased in the intervention group compared with the baseline, and it was significantly higher in this group than in the control group (P < 0.001). Although the serum level of MDA significantly increased in the control group, it significantly reduced in the intervention group after the 10th day (<0.001). Table2. Biomarkers of oxidative stress and inflammation according to randomly assigned treatment group Variables Control group n=33 Intervention group n=34 P-value Plasma 25OHD (ng/mL) Baseline 24.52±14.47 12.7621.6± 0.38 a Day 10 22.56±14.53 23.65±13.03 0.74 a P-value 0.01 <0.001 Changes -1.95±4.51 2.04±2.57 <0.001 a hs-CRP (ng/mL) Baseline 17015 (3668-30775) 17055 (3872-31140) 0.88 b Day 10 21574 (6487-32329) 12257 (2370-24149) 0.01 b P-value 0.11 <0.001 Changes 1419(-1571,4357) -1899(-5984,-1121) <0.001 b IL-6(pg/ml) Baseline 56.05±16.35 63.75±23.66 0.12 a Day 10 60.99±11.89 56.98±25.41 0.41 a P-value 0.01 <0.001 Changes 4.94±11.13 -8.44±10.54 <0.001 a MDA(µM) Baseline 6.33±3.48 7.35±2.82 0.91 a Day 10 8.07±3.36 5.64±2.56 0.001 a P-value <0.001 <0.001 Changes 1.74±2.09 -1.88±0.99 <0.001 a TAC(mM) Baseline 0.34(0.29-0.49) 0.36(0.30-0.46) 0.65 b Day 10 0.29(0.21-0.42) 0.42(0.35-0.57) 0.001 b P-value <0.001 <0.001 Changes -0.03(00.13,0.01) 0.85(0.03-0.13) <0.001 b a Independent Samples T Test; b Mann-witheny U Abbreviations: hs-CRP: High sensitive C-Reactive Protein, IL-6: Interlukin-6, MDA: Malondialdehyde, TAC: Total Antioxidant Capacity Clinical outcomes Among clinical outcomes, only the 28-day IFD was significantly different between the groups (p=0.028), but 28-day VFD and HFD were not significantly different between the two groups. Furthermore, a between-group comparison showed no significant differences in other clinical outcomes, including in-hospital mortality, and 90-day mortality (P >0.05) (Table 3). Table3. Clinical outcomes according to randomly assigned treatment group Variables Control group n=33 Intervention group n=34 P-value 28-day VFD (days) 18(16.21) 20(17.75-21.25) 0.12 a 28-day IFD (days) 20(16.5-21) 21(19.75-23) 0.028 a 28-day HFD (days) 16(14-18) 18(15-19) 0.13 a Mortality In hospital mortality, n(%) 8(24.2) 5(14.7) 0.23 b 90-day mortality, n(%) 10(30.3) 9(26.5) 0.72 b a Mann–Whitney U test b chi-square-tests Abbreviations: HFD: Hospital-free day, IFD: ICU-free day, MVFD: Mechanical ventilation-free day. Mortality at 90 days was numerically higher among the control group than the intervention group, but the difference was not statistically significant (30.3% versus 26.5%, P =0.72). Kaplan-Meier analysis compared 90-day survival time between groups (Figure). Although the curves diverged visually between the two groups, the difference assessed by log rank was not statistically significant (P =0.66). Likewise, the Cox proportional hazards model, adjusting for APACHE II score demonstrated a no significant difference between to group according to 90-day survival (HR 0.55; 95% CI 0.21-1.41: P 0.22) (Table 4). Table4. Univariate and multivariate cox regression for 28-and 90-day survival Intervention Group Univariate Model 1 Adjusted Model 2 HR 95%CI P value HR 95%CI P value 90-Day survival 0.81 0.33-2.01 0.66 0.55 0.21-1.4 0.22 1 Univariate Model: Unadjusted, 2 Adjusted Model: Adjust for APACHI II score Discussion The objective of this randomized, double-blind clinical trial was to evaluate whether oral vitamin D and intravenous vitamin C supplementation could enhance inflammation, oxidative stress, and clinical outcomes in patients with ARF admitted to the ICU. The results demonstrated significant reductions in inflammatory markers, such as IL-6 and hs-CRP, in the intervention group, while the control group experienced increased levels of these indices. Additionally, the intervention group displayed significantly higher serum TAC levels and lower MDA levels compared to baseline measurements and the control group. In contrast, the control group exhibited a decline in TAC levels and an increase in MDA levels from their initial measurements. Furthermore, our findings indicated that the concurrent administration of vitamin D and vitamin C over a 10-day period in ARF patients was independently associated with a reduced length of ICU stay. Notably, the intervention group had shorter hospital stays, reduced mechanical ventilation requirements, and lower in-hospital and 90-day mortality rates compared to the control group; however, these differences were not statistically significant. Overall, our results suggest that supplementation with vitamins D and C for 10 days may improve markers of inflammation and oxidative stress in critically ill ARF patients, likely due to the immunomodulatory, anti-inflammatory, and antioxidant properties of these vitamins. Nonetheless, significant improvements in clinical outcomes were not observed, which may be attributed to the trial being underpowered to analyze such outcomes, including mortality rates, because of its small sample size evaluated through changes in IL-6 levels. ARF is a heterogeneous syndrome and widespread term describing acute hypoxemia and hypercapnia, either alone or in combination, that can develop due to hypoventilation, low inspired oxygen fraction, ventilation and perfusion mismatch, shunt, or diffusion limitation, resulting in abnormalities in oxygen utilization or tissue hypoxia. Underlying causes of ARF can be categorized based on the organ involved in respiration, including airway diseases, respiratory pump failure, respiratory center failure, and failure to achieve elevated metabolic needs. Among them, diseases with respiratory origins, such as COPD, ARDS, pleural effusion, and pneumonia, are the most common causative disorders for ARF in which inflammation and oxidative stress are crucial mechanisms. According to the underlying disease, tissue hypoxia, and mechanical ventilation-induced inflammation and oxidative stress, vitamins D and C have the potential roles in modulating its development. On the other hand, most of the patients with ARF are admitted to the ICU, and the prevalence of vitamin D deficiency is extensively documented within the critically ill population, which is associated with increased infection risk, ICU and hospital length of stay, and mechanical ventilation duration [18, 21, 29-32]. Vitamin D is widely known for its vital role in inflammatory pathways, immunomodulatory effects, and maintaining musculoskeletal health, which may be involved in ARF generation and development [33]. However, its relationship with respiratory health and muscular function still needs to be more adequately understood in the current literature. In non-critically ill individuals, a deficiency in 25-hydroxyvitamin D (25(OH)D) has been correlated with the presence of chronic obstructive pulmonary disease (COPD) and various respiratory symptoms[30, 34]. The association emphasizes the potential benefits of vitamin D in respiratory health, indicating a need for more research to explore its effects on chronic respiratory conditions. Understanding this relationship could suggest new therapeutic approaches and interventions aimed at improving respiratory outcomes[30]. Furthermore, vitamin D has anti-inflammatory, immunomodulatory, and antioxidant properties, recommending its potential utility in managing respiratory diseases with an inflammatory etiology[35-37]. The findings suggest that vitamin D supplementation may have beneficial effects on the outcomes of critically ill patients experiencing respiratory deficiency. So, these highlight the potential importance of vitamin D in managing such patients and warrant further investigation into its role in improving clinical outcomes in critical care settings. Consistent with our findings, Singh et al. conducted a systematic review that illustrates the association between Vitamin D supplementation and a reduction in both the duration of stay in the intensive care unit for critically ill patients[24]. However their research encompassed patients with a range of medical conditions necessitating ICU-level support, including those suffering from sepsis or septic shock, individuals in need of neurocritical care, and patients solely diagnosed with ventilator-associated pneumonia. In a randomized, double-blind, placebo-controlled, single-center trial(The VITdAL-ICU Randomized Clinical Trial) conducted by Amrein et al., compared with the placebo, supplementation with high-dose of vitamin D3(540,000 IU followed by monthly maintenance doses of 90,000 IU for 5 months) could not decline the length of hospital stay, in-hospital mortality, or 6-month mortality[29] that is same of our finding. However, there are some differences, including the study population (medical and surgical ICU patients) and the bolus dosage of vitamin D supplementation, rather than continuous administration. Similar to our findings, Hu et al. conducted a retrospective cohort study, suggesting that vitamin D supplementation in ARF patients may decrease in-hospital and ICU mortality rates [27]. Despite having a larger sample size compared to our trial, their study lacks obviousness regarding the specific type, dosage, and duration of vitamin D supplementation used, as well as the underlying diseases responsible for ARF. This ambiguity raises concerns about the reliability and comparability of their results. In line with our findings, Han et al. showed that supplementation with vitamin D (100,000 IU vitamin D 3 for five days) in mechanically-ventilated critically ill adult patients potentially ameliorates the oxidative stress that was assessed through glutathione disulfide concentration[38]. In relation to vitamin C, previous studies have shown that vitamin C levels in patients admitted to the ICU were significantly lower than those in the control group. Moreover, a notable decline in vitamin C levels was observed during the patients' stay in the ICU[16, 39, 40]. While enteral supplementation with vitamin C did not normalize plasma levels, high-dose intravenous supplementation effectively achieved normal levels and above[17, 41-43]. Research on vitamin C supplementation in critically ill patients has yielded inconsistent findings. Fowler et al. conducted a study investigating the effects of intravenous vitamin C infusion (50 mg/kg in dextrose 5% every 6 hours for 96 hours) on organ failure scores and biological markers related to inflammation, particularly CRP levels, and vascular injury, as indicated by thrombomodulin levels, in patients diagnosed with sepsis and acute respiratory distress syndrome (ARDS). Their findings, in contrast to ours, suggested that a 96-hour administration of vitamin C did not result in statistically significant improvements in organ dysfunction scores or the modulation of inflammatory markers and indicators of vascular injury compared to placebo control[44]. However, compared to our study, the duration of vitamin C administration was lower, and the patient groups differed. It’s also worth mentioning that not assessing additional relevant markers leaves gaps in the analysis, which might make it harder to draw solid conclusions. To truly grasp the full picture, a more comprehensive evaluation that examines a broader range of markers would be extremely helpful. Concurrent with these findings in 2018, Zhang et al. conducted a systematic review encompassing five studies involving 142 critically ill patients (trauma, burn, surgical and medical ICU). Their analysis indicated that intravenous vitamin C had vasopressor-sparing effects and diminished the necessity for mechanical ventilation. However, it did not significantly affect overall mortality rates[19]. Mahmoodpoor et al. studied high doses of vitamin C (60 mg/kg/day via continuous infusion) in critically ill pneumonia patients, finding reduced inflammation, shorter mechanical ventilation duration, and lower vasopressor use, but no significant effect on mortality rates[17]. Critically ill patients in the catabolic phase experience oxidative stress, hyperinflammation, mitochondrial dysfunction, and cellular immune dysfunction. These conditions result in an increased demand for micronutrients and trace elements with antioxidant and anti-inflammatory properties compared to individuals in good health. Conversely, micronutrient deficiencies are prevalent among critically ill patients, primarily due to heightened metabolic demands associated with underlying conditions, reduced nutritional intake, treatments in the ICU, medications, and prior malnutrition. Consequently, the supplementation of micronutrients holds promise for enhancing organ function and improving clinical outcomes, given their roles in various biological pathways and enzymatic processes. It is important to note that our ineffective results in improving clinical outcomes may be influenced by an insufficient sample size, which was determined based on changes in IL-6 levels and was inadequate to demonstrate changes in clinical outcomes. Strengths and Limitations The primary strength of this study lies in evaluating two markers for inflammation and oxidative stress along with clinical outcomes, so this methodology enables a more comprehensive interpretation. In addition, the blinding of oral vitamin D and intravenous vitamin between the two groups is another strength of this trial. However, despite this strength, our trial faced several limitations. One notable limitation is the sample size, which was determined to assess IL-6 as the primary outcome between the intervention and control groups due to the deprivation of financial resources. Consequently, the sample size is insufficient for detecting differences in the clinical outcomes. Conclusion According to our findings, daily Supplementation with 5,000 IU of vitamin D drops and 2,000 mg intravenous vitamin C in critically ill ARF patients for 10 days could decrease inflammation markers, oxidative stress indices, and the duration of ICU stay but did not affect the length of mechanical ventilation, hospital stay, or mortality. Therefore, future trials with larger sizes that could reach sufficient levels for evaluating clinical outcomes are necessary. Abbreviations 25(OH)D: 25-hydroxyvitamin D ARDS: Acute Respiratory Distress Syndrome ARF: Acute respiratory failure APACHE II: Acute Physiology and Chronic Health Evaluation II COPD: Chronic Obstructive Pulmonary Disease ELISA: Enzyme-Linked Immunosorbent Assay IBW: Ideal Body Weight ICU: Intensive Care Unit IFD: ICU Free Days HFD: Hospital Free Days HPLC: high-performance liquid chromatography IL-6: Interleukin-6 hs-CRP: High-sensitivity C-reactive protein MDA: Malondialdehyde MFD: Mechanical Ventilation-Free Days NUTRIC: Nutrition Risk in Critically Ill TAC: Total Antioxidant Capacity RCT: Randomized Controlled Trial SOFA: Sequential Organ Failure Assessment Declarations Acknowledgments The authors express gratitude to all the study participants, the respiratory ICU staff of Firoozgar Hospital, and others who helped us conduct this study. Supplementary Information Not applicable Authors’ contributions All authors contributed equally to the study concept and design, acquisition of subjects and/or data, analysis and interpretation of data, and manuscript preparation. Funding This study is funded by the Iran University of Medical Sciences, Tehran, Iran (grant no: 1402-2-2-26371). The funders have no role in the design of the trial, procedures, intervention, collection, evaluation, and data analysis. Data availability The datasets used and analysed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate Ethical approval was obtained from the Committee of Iran University of Medical Sciences (IR.IUMS.REC.1402.210). Before participating in the research project, all participants must provide and sign a written informed consent form detailing the terms and conditions. Upon signing the consent form, participants will be required to indicate their consent for utilizing their data in the event of withdrawal. Furthermore, researchers will seek participants' authorization to share pertinent data with individuals affiliated with the participating universities or regulatory authorities. It is important to note that biological specimens will not be gathered for storage purposes in this trial. The study has been registered at https://irct.behdasht.gov.ir/. Number: IRCT20090822002365N29 . Consent to publication All authors approved the final version of the manuscript and agreed to all aspects of the work being published. Competing interests The authors declare no competing interests. Author Details 1.Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran 2. Department of Internal Medicine, School of Medicine, Firoozgar General Hospital, Iran University of Medical Sciences (IUMS), Tehran, Iran. 3. Firoozgar Clinical Research Development Centre (FCRDC), Iran University of Medical Sciences (IUMS), Tehran, Iran. 4. Department of Clinical Nutrition and Dietetics, National Nutrition and Food Technology Research Institute, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran 5. Department of Statistics and Epidemiology, School of Public Health, Tabriz University of Medical Sciences, Tabriz, Iran 6. Department of Pediatric Nursing, School of Nursing and Midwifery, Iran Medical Sciences University, Tehran, Iran References Scala R, Heunks L. Highlights in acute respiratory failure. Eur Respir Rev, 2018. 27(147). Villgran VD, et al. Acute Respiratory Failure. Crit Care Nurs Q. 2022;45(3):233–47. Yang P, Esper AM. Acute Respiratory Failure: Problems Solved and Unsolved. Crit Care Clin. 2024;40(2):xiii–xv. Chen L, Rackley CR. Diagnosis and Epidemiology of Acute Respiratory Failure. Crit Care Clin. 2024;40(2):221–33. Franca SA, et al. The epidemiology of acute respiratory failure in hospitalized patients: a Brazilian prospective cohort study. J Crit Care. 2011;26(3):e3301–8. Lavender Z, Sandor P, Ricker MA. Breathe In, Breathe Out: Respiratory Considerations in the Intensive Care Unit. Physician Assistant Clin. 2019;4(2):361–71. Ling RR, et al. Epidemiology of acute hypoxaemic respiratory failure in Australian and New Zealand intensive care units during 2005–2022. A binational, registry-based study. Intensive Care Med. 2024;50(11):1861–72. Abebe KG, Koster Y, Bimrew M. Prevalence of Respiratory Failure And Associated Factors In Adult Intensive Care Unit of Saint Paul’s And Addis Ababa Burn, Emergency And Trauma Hospital, Ethiopia 2020. 2023. Peña-López Y, et al. Limiting ventilator-associated complications in ICU intubated subjects: strategies to prevent ventilator-associated events and improve outcomes. Expert Rev Respir Med. 2018;12(12):1037–50. Ni YN, et al. The effect of hyperoxia on mortality in critically ill patients: a systematic review and meta analysis. BMC Pulm Med. 2019;19(1):53. Haribhai S, Mahboobi SK. Ventilator Complications, in StatPearls. 2024, StatPearls Publishing Copyright © 2024, StatPearls Publishing LLC.: Treasure Island (FL). Ren J, et al. Association of lactate/albumin ratio with in-hospital mortality in ICU patients with acute respiratory failure: A retrospective analysis based on MIMIC-IV database. Med (Baltim). 2023;102(39):e35410. Colgan SP, Campbell EL, Kominsky DJ. Hypoxia and Mucosal Inflammation. Annu Rev Pathol. 2016;11:77–100. Casaer MP, Bellomo R. Micronutrient deficiency in critical illness: an invisible foe? Intensive Care Med. 2019;45(8):1136–9. Cutuli SL et al. Vitamin D Status and Potential Therapeutic Options in Critically Ill Patients: A Narrative Review of the Clinical Evidence. Diagnostics (Basel), 2022. 12(11). Koekkoek WAC, et al. Micronutrient deficiencies in critical illness. Clin Nutr. 2021;40(6):3780–6. Mahmoodpoor A, et al. Effect of Vitamin C on mortality of critically ill patients with severe pneumonia in intensive care unit: a preliminary study. BMC Infect Dis. 2021;21(1):616. Weng H, et al. Randomised trials of vitamin D(3) for critically ill patients in adults: systematic review and meta-analysis with trial sequential analysis. Intensive Care Med. 2017;43(2):277–8. Zhang M, Jativa DF. Vitamin C supplementation in the critically ill: A systematic review and meta-analysis. SAGE Open Med. 2018;6:2050312118807615. P LL, Lamontagne F. Vitamin C for the critically ill: Is the evidence strong enough? Nutrition. 2019;60:185–90. Amrein K, Christopher KB, McNally JD. Understanding vitamin D deficiency in intensive care patients. Intensive Care Med. 2015;41(11):1961–4. Amrein K, Oudemans-van HM, Straaten, Berger MM. Vitamin therapy in critically ill patients: focus on thiamine, vitamin C, and vitamin D. Intensive Care Med. 2018;44(11):1940–4. Langlois PL, D'Aragon F, Manzanares W. Vitamin D in the ICU: More sun for critically ill adult patients? Nutrition. 2019;61:173–8. Singh S, et al. Vitamin D Supplementation in Critically Ill Patients: A Meta-Analysis of Randomized Controlled Trials. Cureus. 2022;14(4):e24625. Carpagnano GE, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest. 2021;44(4):765–71. Thickett DR, et al. Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients: a retrospective cohort study. BMJ Open Respir Res. 2015;2(1):e000074. Hu S, et al. Vitamin D supplementation is beneficial in improving the prognosis of patients with acute respiratory failure in the intensive care unit: a retrospective study based on the MIMIC-IV database. Front Med (Lausanne). 2023;10:1271060. Dastan F, et al. Effects of High-Dose Vitamin D Replacement on the Serum Levels of Systemic Inflammatory Biomarkers in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Copd. 2019;16(3–4):278–83. Amrein K, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312(15):1520–30. Williams S, Heuberger R. Outcomes of Vitamin D Supplementation in Adults Who are Deficient and Critically Ill: A Review of the Literature. Am J Ther, 2016. 23(6): pp. e1890-e1902. Li Y, Ding S. Serum 25-Hydroxyvitamin D and the risk of mortality in adult patients with Sepsis: a meta-analysis. BMC Infect Dis. 2020;20(1):189. Braun AB, et al. Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill. Crit Care Med. 2012;40(12):3170–9. Rimaniol JM, Authier FJ, Chariot P. Muscle weakness in intensive care patients: initial manifestation of vitamin D deficiency. Intensive Care Med. 1994;20(8):591–2. Hendryx M, Luo J. A test of vitamin D benefits on respiratory health mediated through inflammatory markers. Chron Respir Dis. 2015;12(1):24–30. Hamza FN et al. Immunomodulatory Properties of Vitamin D in the Intestinal and Respiratory Systems. Nutrients, 2023. 15(7). Hansdottir S, Monick MM. Vitamin D effects on lung immunity and respiratory diseases. Vitam Horm. 2011;86:217–37. Herr C, et al. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer. Respir Res. 2011;12(1):31. Han JE, et al. Oxidative stress in critically ill ventilated adults: effects of vitamin D(3) and associations with alveolar macrophage function. Eur J Clin Nutr. 2018;72(5):744–51. Carr AC, et al. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. 2017;21(1):300. Berger MM. Vitamin C requirements in parenteral nutrition. Gastroenterology. 2009;137(5 Suppl):S70–8. van Zanten AR, et al. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. JAMA. 2014;312(5):514–24. Fowler AA 3, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32. Long CL, et al. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res. 2003;109(2):144–8. Fowler AA 3rd, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019;322(13):1261–70. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 29 Sep, 2025 Read the published version in Nutrition Journal → Version 1 posted Editorial decision: Revision requested 18 Jun, 2025 Reviews received at journal 17 Jun, 2025 Reviews received at journal 14 Jun, 2025 Reviewers agreed at journal 10 Jun, 2025 Reviewers agreed at journal 29 May, 2025 Reviewers invited by journal 29 May, 2025 Editor assigned by journal 28 May, 2025 Submission checks completed at journal 19 May, 2025 First submitted to journal 16 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6683114","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":464754771,"identity":"81dea6c1-7ff4-4e85-991a-a62bfc087c30","order_by":0,"name":"Aynaz velayati","email":"","orcid":"","institution":"Iran University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Aynaz","middleName":"","lastName":"velayati","suffix":""},{"id":464754772,"identity":"7489eb54-2552-42c7-8029-37baebba360d","order_by":1,"name":"Mohammadreza vafa","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAx0lEQVRIiWNgGAWjYPACOQZ+BgY2krQYM0g2kKzF4ACxWszb2x9+5qkxkDe+kfzswYcKBnl+sQP4tcicOZAszXPMwHDbjTRzwxlnGAxnzk7Ar0VCIuGA5Ay2P4zbbiSYSfO2MSQY3CakRf5h888Z/wzsN89I/0akFglmNomPbQaJGyRyiLWFJ43N4mOfQfKMM2/KJGeckSDCL+zHH99I+GZg29+evk3iQ4WNPL80AS0IIABWKUGschDgP0CK6lEwCkbBKBhJAACm5D+BilaXuwAAAABJRU5ErkJggg==","orcid":"","institution":"Iran University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Mohammadreza","middleName":"","lastName":"vafa","suffix":""},{"id":464754773,"identity":"f3fe09b7-994c-415e-bc16-1e0b909d17a0","order_by":2,"name":"Mahdi Yadollahzadeh","email":"","orcid":"","institution":"Iran University of Medical Sciences (IUMS)","correspondingAuthor":false,"prefix":"","firstName":"Mahdi","middleName":"","lastName":"Yadollahzadeh","suffix":""},{"id":464754774,"identity":"71008496-933e-4314-9ef0-23f59eef300e","order_by":3,"name":"Zahra Vahdat Shariatpanahi","email":"","orcid":"","institution":"National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Zahra","middleName":"Vahdat","lastName":"Shariatpanahi","suffix":""},{"id":464754775,"identity":"9695ca30-a055-4752-812c-67bbc51888f0","order_by":4,"name":"parvin sarbakhsh","email":"","orcid":"","institution":"Tabriz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"parvin","middleName":"","lastName":"sarbakhsh","suffix":""},{"id":464754776,"identity":"e4a361e7-7f80-4571-b82e-6a69229b9a3c","order_by":5,"name":"Hamidreza salemi","email":"","orcid":"","institution":"Iran Medical Sciences University","correspondingAuthor":false,"prefix":"","firstName":"Hamidreza","middleName":"","lastName":"salemi","suffix":""}],"badges":[],"createdAt":"2025-05-16 19:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6683114/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6683114/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12937-025-01214-5","type":"published","date":"2025-09-29T15:56:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83897088,"identity":"115413a3-1b8a-474d-887a-4a6c4807bca0","added_by":"auto","created_at":"2025-06-04 08:54:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":506382,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6683114/v1/873cabe0264e484a76a64aa1.jpg"},{"id":92883696,"identity":"6e1b7940-9926-4905-8600-23b6f1884073","added_by":"auto","created_at":"2025-10-06 16:08:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1863859,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6683114/v1/fb094b8f-0ef1-493d-8a2b-2a5c1e93ba84.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical randomized trial of vitamin D and C supplementation in critically ill patients with respiratory failure","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute respiratory failure (ARF) is a critical organ dysfunction characterized by hypoxia, which can occur with or without hypercapnia. [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. It is a leading cause of admissions to intensive care units (ICUs), accounting for approximately 30% of all ICU admissions[\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. ARF is associated with significant use of medical resources, increased demands on healthcare staff, longer durations of mechanical ventilation, extended stays in both the ICU and the hospital, and a high mortality rate that exceeds 40%[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. While mechanical ventilation (MV), whether invasive (IMV) or non-invasive (NIV), can provide vital support and time to treat underlying causes of ARF (1,7), it can also lead to complications such as ventilator-induced lung injury and oxygen toxicity[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These complications may trigger inflammatory responses, activate cytokines, and recruit other inflammatory mediators, producing reactive oxygen species (ROS) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn response to hypoxia in ARF, cells increasingly depend on anaerobic respiration, which leads to heightened glycolysis and lactic acid accumulation. This metabolic shift activates pathways that promote the formation of ROS and pro-inflammatory mediators. In summary, inflammation and oxidative stress\u0026mdash;driven by underlying health issues, tissue hypoxemia, and mechanical ventilation\u0026mdash;play a crucial role in the development of ARF and contribute to its adverse outcomes [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOn the other hand, vitamin deficiencies, especially vitamin D (Over 80%) and vitamin C (up to 30%), are common in critically ill patients due to reduced intake and increased requirements[\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], which worsens the inflammation situation, oxidative conditions and clinical outcomes, including duration of MV, ICU, and hospital stay, and mortality rate due to their anti-inflammatory and antioxidant roles[\u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Despite the limited evidence concerning vitamin levels in ARF patients admitted to ICU, prior research has demonstrated that critically ill patients suffering from ARF due to Coronavirus disease 19 (COVID-19) display a distinctly elevated prevalence of vitamin D deficiency [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Specifically, those with preadmission serum vitamin D levels below 30 ng/ml are at an elevated risk of developing ARF compared to individuals with sufficient vitamin D levels[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Recent studies have indicated that vitamin D supplementation could play a critical role in decreasing in-hospital and ICU mortality rates for patients with ARF who are admitted to the ICU [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevious researches evaluated the impact of these vitamins in critically ill patients, which has yielded conflicting findings. Despite the high prevalence of ARF in the ICU and widespread deficiencies of vitamins D and C in these patients, no study has specifically assessed the effects of these vitamins on ARF patients. Therefore, this article aims to examine the effects of simultaneous oral vitamin D and intravenous vitamin C supplementation on inflammatory markers, oxidative stress, and clinical outcomes in patients with respiratory failure in the intensive care unit.\u003c/p\u003e"},{"header":"Methods and materials","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and ethics patients\u003c/h2\u003e \u003cp\u003eThe double-blind randomized placebo-controlled trial was conducted over one year (November 2023-Novamber 2024), involving patients over 18 and under 75 years old admitted to the ICU of Firoozgar Hospital in Tehran, Iran.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics\u003c/h3\u003e\n\u003cp\u003eThe study protocol was registered at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://irct.behdasht.gov.ir/\u003c/span\u003e\u003cspan address=\"https://irct.behdasht.gov.ir/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (No: IRCT20090822002365N29), and it was ethically approved by the Committee of Iran University of Medical Sciences (registration IR.IUMS.REC.1402.210). The study was developed and conducted in accordance with the Declaration of Helsinki and was reported based on the Consolidated Standards of Reporting Trials (CONSORT) guidelines.\u003c/p\u003e\n\u003ch3\u003eSubjects and eligibility criteria\u003c/h3\u003e\n\u003cp\u003eARF Patients eligible for this study must have been admitted to the ICU within 24 hours and consented to participate. They should not have a history of nervous system disease that prevents discharge from mechanical ventilation, hypercalcemia (total calcium\u0026thinsp;\u0026gt;\u0026thinsp;10.6 mg/dL), hyperphosphatemia (\u0026gt;\u0026thinsp;1.45 mmol/L), sarcoidosis, tuberculosis, AIDS, liver or renal failure, and gout. Additionally, they should not have participated in other randomized clinical trials before or after ICU admission, be pregnant or breastfeeding, or have consumed vitamin D or vitamin C in the 30 days before ICU admission. Exclusion criteria were death or discharge from the ICU sooner than 3 days, request for stop intervention or unwillingness to continue studying, and developing contraindications for administering vitamin D and vitamin C based on the attending physician's opinion at the time of the study.\u003c/p\u003e\n\u003ch3\u003eRandomization and blinding\u003c/h3\u003e\n\u003cp\u003eA total of 82 consecutive patients were evaluated for eligibility. Patients were excluded after the initial assessment due to mortality within 3 days in the ICU, discharge from this unit in less than 3 days, or lack of willingness to continue. As a result, eligible patients were randomly assigned to either the intervention or control groups at a 1:1 ratio using the block randomization technique. A blinded randomization list of quadruple blocks will be generated through a web-based system for clinical trials (www.sealedenvelope.com\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.sealedenvelope.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study is structured as a double-blind study, meaning that throughout the duration of the research, the participants, researchers, healthcare personnel, and the statistician will be unaware of the group allocation. To ensure effective blinding, the drug (consisting of a vitamin D supplement and serum containing vitamin C) and the placebo (comprising miglyol and serum without vitamin C) were designed to be indistinguishable in terms of smell, color, and packaging. The only individual informed about the treatment was the nurse overseeing the study intervention.\u003c/p\u003e\n\u003ch3\u003eIntervention and Adherence\u003c/h3\u003e\n\u003cp\u003eThe intervention lasted between 3 and 10 days, depending on the duration of the patient's ICU stay. Patients in the intervention group were administered five mL of vitamin D drops (containing 5000 IU of 25-hydroxyvitamin D) via oral intake or enteral formula and two thousand mg of vitamin C via continuous infusion or normal saline that was prepared and administrated for patients by a trained pharmacist who did not engage in any part of the study. Conversely, during this period, the control group received a placebo (containing Miglyol) instead of vitamin D drops and an infusion without vitamin C. Vitamin D was given in enteral formula through a feeding tube for patients receiving enteral feeding.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSafety evaluations\u003c/h2\u003e \u003cp\u003eTo ensure compliance, tolerability and potential adverse effects, the main investigator (A.V) reviewed the nurse's records daily.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy endpoints\u003c/h3\u003e\n\u003cp\u003eThe primary outcome of the study was the change in serum interleukin-6 (IL-6), an inflammation marker. Secondary outcomes included changes in serum C-reactive protein (CRP), total antioxidant capacity (TAC), malondialdehyde (MDA), and clinical outcomes such as 90-day mortality and days free from hospitalization, ICU admission, and mechanical ventilation.\u003c/p\u003e\n\u003ch3\u003eAssessment of clinical, respiratory, and anthropometric parameters\u003c/h3\u003e\n\u003cp\u003eIn this clinical trial, eligible patients were enrolled after obtaining written informed consent from either the patient or their relatives. Following this, a comprehensive profile sheet capturing demographic information, including age, sex, comorbidities (such as hypertension, diabetes, dyslipidemia), the underlying cause of respiratory failure, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, was completed for each patient. Arterial blood gases and mechanical ventilation respiratory parameters were recorded for each patient. Daily assessments were performed for each patient to evaluate organ failures, including cardiovascular, central nervous system, coagulation, hepatic, and renal failures. Following their discharge from the ICU, patients underwent a 90-day monitoring period to assess rehospitalization and mortality rates without any additional intervention. The 25(OH)D level was measured at the beginning and end of the intervention using high-performance liquid chromatography (HPLC) to show any changes. Vitamin D deficiency is defined as a 25(OH)D level lower than 20 ng/mL, insufficiency ranging from 21 to 30 ng/mL, and sufficiency at levels higher than 30 ng/mL. The Nutrition Risk in Critically Ill (NUTRIC) score was calculated at the start and end of the trial using relevant questionnaires. The Sequential Organ Failure Assessment (SOFA) score was measured every day by ICU nurses. If available, the patients' height and weight were recorded from their medical records, otherwise recumbent height assessed by using a flexible tape with an accuracy of 0.5 cm and weight were calculate through ideal body weight (IBW). Nutritional parameters including routes of nutrition intake (oral or enteral) and energy and protein intake percentages were recorded for each patient daily.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMeasurement of blood biochemical parameters\u003c/h2\u003e \u003cp\u003eA trained healthcare professional collected a 5-milliliter blood sample from a vein in the arm using a vacutainer tube before and after the intervention. The sample was promptly chilled and transported to the laboratory for processing. Upon arrival, it was centrifuged at 3000 revolutions per minute at 4 degrees Celsius for 10 minutes to separate the serum, which was then stored at -80 degrees Celsius until it was ready for biochemical analysis. Inflammatory markers such as IL-6 and hs-CRP were quantified using enzyme-linked immunosorbent assay (ELISA) and specific ELISA kits for cytokines. Additionally, ELISA kits were used to measure MDA levels in the serum, while spectrophotometric methods were employed to assess TAC levels as an oxidative marker.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eData management\u003c/h2\u003e \u003cp\u003eEach patient was assigned a unique ID and assured that their data would remain confidential. All information, including questionnaires, records, and laboratory results, was coded by a data management team and entered into IBM SPSS Statistics v 27.0 software. The coded data was subsequently provided to a study statistician for analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eThe sample size for this Randomized Controlled Trial (RCT) comparing IL-6 as the primary outcome between the intervention and control groups was determined using Stata 17 software. We employed a two-way comparison formula and referred to a previous study[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], considering an effect size corresponding to a 40% reduction in IL-6, 80% power, and a 0.05 alpha error. This calculation indicated that 32 participants were needed for each group. Allowing for a 10% dropout rate, our target is to recruit 70 patients (35 patients per group).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe intention-to-treat principles used for main analyses. The normality of these variables was evaluated using the Kolmogorov‒Smirnov test. Continuous variables were presented as Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;Standard Deviation (SD) or median (interquartile range) as appropriate. Independent t-tests or the Mann‒Whitney U test will be used to compare normally or non-normally distributed indicators, respectively, between the two groups. Nominal variables were shown as frequencies (%) and analyzed using the chi-square test. To assess the duration of patients' stay in the ICU and hospital and their need for mechanical ventilation, we calculated the number of ICU and hospital-free days (IFD and HFD) and mechanical ventilation-free days(MFD) in 28 days after ICU admission. The 28-day and 90-day mortality rates were compared between the two groups using survival analysis and a Cox regression model, with the time of death recorded. The significance level for the tests is 0.05, and all analyses were conducted using IBM SPSS Statistics v 27.0 software. There are no planned subgroup analyses or interim analyses for this trial.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eDemographic and nutritional characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs per the exclusion criteria, a total of 3 out of 70 patients were excluded from the study. Of these included patients, two patients were excluded because of discharge and death before 3 days of admission in the ICU, and one patient was due to unwillingness to continue studying. As a result, the study was completed by 67 patients, including 24 males in the control group and 19 males in the intervention group, which is not statistically significant (Fig. 1).\u003c/p\u003e\n\u003cp\u003eThe general characteristics, comorbidities, severity of illness, baseline laboratory parameters, and nutritional variables of patients are presented in Table 2. There were no significant differences in the prevalence of comorbidities, the APACHE II and SOFA scores, laboratory and respiratory parameters and nutritional indices, such as nutritional routes and energy and protein intake, between the intervention and the control groups (P \u0026gt; 0.05).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable1. Demographic and nutritional characteristics of patients according to randomly assigned treatment group\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e33\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e34\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGeneral characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eAge (Mean\u0026plusmn; SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e66.76\u0026plusmn;9.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e66.12\u0026plusmn;8.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.77\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eMale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e19(57.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e24(70.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.26\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eSmoking status (yes)n%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e12(36.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e10(29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.54\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eAddiction, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e7(21.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e9(26.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.61\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnderlying disease n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eCOPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e11(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e11(32.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.28\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003epneumonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e8(24.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e11(32.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003ePleural effusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e8(24.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e2(5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eARDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e3(9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e5(14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eOthers\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e3(9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e5(14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eRespiratory disease, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e32(96.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e31(91.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.31\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eHypertension, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e19(57.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e19(55.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.88\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eDiabetes, n(%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e9(27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e9(26.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.94\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eDyslipidemia, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e16(48.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e12(35.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e0.27\u003c/span\u003e\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSeverity of illness\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eAPACHE II score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e16(14-22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e17(14-23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.49\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eSOFA score admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e3(2-11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e5.5(2.75-10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.29\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eNutric score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e5(4-7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e5(5-7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.17\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLaboratory parameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eAdmission Blood glucose (mg/dL) (Mean\u0026plusmn; SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e172.45\u0026plusmn;62.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e145.29\u0026plusmn;91.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.18\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eCreatinine mg/dl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e1.14\u0026plusmn;0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e1.34\u0026plusmn;0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.11\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eWBC count, 10\u003csup\u003e9\u003c/sup\u003e /L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e9.88\u0026plusmn;3.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e9.82\u0026plusmn;4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.95\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eRBC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e4.46\u0026plusmn;0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e425\u0026plusmn;0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.33\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eHemoglobin, g/dl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e12.20\u0026plusmn;1.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e12.21\u0026plusmn;2.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.99\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eAdmission Albumin (g/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e3.09\u0026plusmn;0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e3.00\u0026plusmn;0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.58\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003ePlasma 25OHD (ng/mL)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e24.52\u0026plusmn;14.47\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e21.06\u0026plusmn;12.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.38\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eDeficiency n(%)\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e14(42.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e18(52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e0.\u003c/span\u003e25\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eInsufficiency n(%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e9(27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e7(20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eSufficient n(%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e9(27.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e8(23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRespiratory parameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eType of \u0026nbsp;ventilation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eVenturi mask, n(%)\u003c/span\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eBipap, n(%)\u003c/span\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eVentilator, n(%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e4(12.1)\u003c/p\u003e\n \u003cp\u003e19(5736)\u003c/p\u003e\n \u003cp\u003e10(30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e6(17.6)\u003c/p\u003e\n \u003cp\u003e19(55.9)\u003c/p\u003e\n \u003cp\u003e9(26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.80\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNutritional parameters\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eNutritional routs\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eOral, n(%)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eEnteral, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e23(69.7)\u003c/p\u003e\n \u003cp\u003e10(30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e24(70.6)\u003c/p\u003e\n \u003cp\u003e10(29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.93\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eMean energy intake (kcal/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e1448.86\u0026plusmn;188.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e1540.75\u0026plusmn;202.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.059\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35px;\"\u003e\n \u003cp\u003eMean protein intake(gr/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25px;\"\u003e\n \u003cp\u003e45.04\u0026plusmn;6.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e47.26\u0026plusmn;6.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.18\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eIndependent Samples T Test; \u003csup\u003eb\u003c/sup\u003e Chi-square test, n (%); \u003csup\u003ec\u0026nbsp;\u003c/sup\u003eMann-Witheny U\u003c/p\u003e\n\u003cp\u003eAbbreviations: ARDS: Acute Respiratory Distress Syndrome; APACHI II score: Acute Physiology and Chronic Health Evaluation II; COPD: Chronic Obstructive Pulmonary Disease; NUTRIC score: Nutrition Risk in Critically Ill; SOFA score: Organ Failure Assessment\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiomarkers of oxidative stress and inflammation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 presents the baseline levels and changes in vitamin D, oxidative stress, and inflammation biomarkers. There were no significant differences in serum vitamin D, oxidative stress, and inflammation parameters levels between the two groups at the baseline (P \u0026gt; 0.05). Serum vitamin D levels decreased\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003esignificantly in the control group during their ICU stay (changes=-1.95\u0026plusmn;4.51 p=0.01). At the same time, they increased in the intervention group (changes=2.04\u0026plusmn;2.57 P\u0026lt;0.001), even though supplementation could not reach a sufficient level\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e(\u0026gt;30 ng/ml) and the mean level of vitamin D is not statistically significant between the two groups(P=0.74).\u003c/p\u003e\n\u003cp\u003eAfter 10 days of intervention, the mean serum levels of IL-6 and hs-CRP were significantly reduced in intervention groups (P\u0026lt;0.001), while inversely, these increased in the control group compared with the baseline.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn the 10th day of the study, the serum level of TAC significantly increased in the intervention group compared with the baseline, and it was significantly higher in this group than in the control group (P \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003eAlthough the serum level of MDA significantly increased in the control group, it significantly reduced in the intervention group after the 10th day (\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable2. Biomarkers of oxidative stress and inflammation according to randomly assigned treatment group\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eVariables\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eControl group\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003en=33\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en=34\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003ePlasma 25OHD (ng/mL)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e24.52\u0026plusmn;14.47\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp dir=\"RTL\"\u003e12.7621.6\u0026plusmn;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.38\u003csup\u003ea\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e22.56\u0026plusmn;14.53\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e23.65\u0026plusmn;13.03\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e0.74\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp dir=\"RTL\"\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChanges\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e-1.95\u0026plusmn;4.51\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e2.04\u0026plusmn;2.57\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e\u0026lt;0.001\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ehs-CRP (ng/mL)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e17015 (3668-30775)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e17055 (3872-31140)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e0.88\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e21574 (6487-32329)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e12257 (2370-24149)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e0.01\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChanges\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e1419(-1571,4357)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e-1899(-5984,-1121)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIL-6(pg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e56.05\u0026plusmn;16.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e63.75\u0026plusmn;23.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e0.12\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e60.99\u0026plusmn;11.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e56.98\u0026plusmn;25.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e0.41\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChanges\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e4.94\u0026plusmn;11.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e-8.44\u0026plusmn;10.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMDA(\u0026micro;M)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e6.33\u0026plusmn;3.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e7.35\u0026plusmn;2.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e0.91\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e8.07\u0026plusmn;3.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e5.64\u0026plusmn;2.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e0.001\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChanges\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e1.74\u0026plusmn;2.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e-1.88\u0026plusmn;0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTAC(mM)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e0.34(0.29-0.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.36(0.30-0.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e0.65\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDay 10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e0.29(0.21-0.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.42(0.35-0.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e0.001\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eChanges\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e-0.03(00.13,0.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 24px;\"\u003e\n \u003cp\u003e0.85(0.03-0.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eIndependent Samples T Test;\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e Mann-witheny U\u003c/p\u003e\n\u003cp\u003eAbbreviations: hs-CRP: High sensitive C-Reactive Protein, IL-6: Interlukin-6, MDA: Malondialdehyde, TAC: Total Antioxidant Capacity\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong clinical outcomes, only the 28-day IFD was significantly different between the groups (p=0.028), but 28-day VFD and HFD were not significantly different between the two groups. Furthermore, a between-group comparison showed no significant differences in other clinical outcomes, including in-hospital mortality, and 90-day mortality (P \u0026gt;0.05) (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable3. Clinical outcomes according to randomly assigned treatment group\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eVariables\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003eControl group\u003c/p\u003e\n \u003cp\u003en=33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003eIntervention group\u003c/p\u003e\n \u003cp\u003en=34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e28-day VFD \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e(days)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e18(16.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e20(17.75-21.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e0.12\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e28-day IFD \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e(days)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e20(16.5-21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e21(19.75-23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e0.028\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e28-day HFD \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e(days)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e16(14-18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e18(15-19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e0.13\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eMortality\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003eIn hospital mortality, \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003en(%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e8(24.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e5(14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e0.23\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e90-day mortality,\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"LTR\"\u003e n(%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e10(30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 28px;\"\u003e\n \u003cp\u003e9(26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 21px;\"\u003e\n \u003cp\u003e0.72\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eMann\u0026ndash;Whitney U test\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e chi-square-tests\u003c/p\u003e\n\u003cp\u003eAbbreviations: HFD: Hospital-free day, IFD: ICU-free day, MVFD: Mechanical ventilation-free day.\u003c/p\u003e\n\u003cp\u003eMortality at 90 days was numerically higher among the control group than the intervention group, but the difference was not statistically significant (30.3% versus 26.5%, P =0.72). Kaplan-Meier analysis compared 90-day survival time between groups (Figure). Although the curves diverged visually between the two groups, the difference assessed by log rank was not statistically significant (P =0.66). \u0026nbsp;Likewise, the Cox proportional hazards model, adjusting for APACHE II score demonstrated a no significant difference between to group according to 90-day survival (HR 0.55; 95% CI 0.21-1.41: P 0.22) (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable4. Univariate and multivariate cox regression for 28-and 90-day survival\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention Group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 32px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariate Model\u003csup\u003e1\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted Model\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e90-Day \u0026nbsp;survival\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e0.33-2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e0.21-1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003e Univariate Model: Unadjusted, \u003csup\u003e2\u003c/sup\u003e Adjusted Model: Adjust for APACHI II score\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe objective of this randomized, double-blind clinical trial was to evaluate whether oral vitamin D and intravenous vitamin C supplementation could enhance inflammation, oxidative stress, and clinical outcomes in patients with ARF admitted to the ICU. The results demonstrated significant reductions in inflammatory markers, such as IL-6 and hs-CRP, in the intervention group, while the control group experienced increased levels of these indices. Additionally, the intervention group displayed significantly higher serum TAC levels and lower MDA levels compared to baseline measurements and the control group. In contrast, the control group exhibited a decline in TAC levels and an increase in MDA levels from their initial measurements. Furthermore, our findings indicated that the concurrent administration of vitamin D and vitamin C over a 10-day period in ARF patients was independently associated with a reduced length of ICU stay. Notably, the intervention group had shorter hospital stays, reduced mechanical ventilation requirements, and lower in-hospital and 90-day mortality rates compared to the control group; however, these differences were not statistically significant. Overall, our results suggest that supplementation with vitamins D and C for 10 days may improve markers of inflammation and oxidative stress in critically ill ARF patients, likely due to the immunomodulatory, anti-inflammatory, and antioxidant properties of these vitamins. Nonetheless, significant improvements in clinical outcomes were not observed, which may be attributed to the trial being underpowered to analyze such outcomes, including mortality rates, because of its small sample size evaluated through changes in IL-6 levels.\u003c/p\u003e\n\u003cp\u003eARF is a heterogeneous syndrome and widespread term describing acute hypoxemia and hypercapnia, either alone or in combination, that can develop due to hypoventilation, low inspired oxygen fraction, ventilation and perfusion mismatch, shunt, or diffusion limitation, resulting in abnormalities in oxygen utilization or tissue hypoxia. Underlying causes of ARF can be categorized based on the organ involved in respiration, including airway diseases, respiratory pump failure, respiratory center failure, and failure to achieve elevated metabolic needs. \u0026nbsp; Among them, diseases with respiratory origins, such as COPD, ARDS, pleural effusion, and pneumonia, are the most common causative disorders for ARF in which inflammation and oxidative stress are crucial mechanisms. According to the underlying disease, tissue hypoxia, and mechanical ventilation-induced inflammation and oxidative stress, vitamins D and C have the potential roles in modulating its development. On the other hand, most of the patients with ARF are admitted to the ICU, and the prevalence of vitamin D deficiency is extensively documented within the critically ill population, which is associated with increased infection risk, ICU and hospital length of stay, and mechanical ventilation duration [18, 21, 29-32]. Vitamin D is widely known for its vital role in inflammatory pathways, immunomodulatory effects, and maintaining musculoskeletal health, which may be involved in ARF generation and development [33]. However, its relationship with respiratory health and muscular function still needs to be more adequately understood in the current literature. In non-critically ill individuals, a deficiency in 25-hydroxyvitamin D (25(OH)D) has been correlated with the presence of chronic obstructive pulmonary disease (COPD) and various respiratory symptoms[30, 34]. The association emphasizes the potential benefits of vitamin D in respiratory health, indicating a need for more research to explore its effects on chronic respiratory conditions. Understanding this relationship could suggest new therapeutic approaches and interventions aimed at improving respiratory outcomes[30]. Furthermore, vitamin D has anti-inflammatory, immunomodulatory, and antioxidant properties, recommending its potential utility in managing respiratory diseases with an inflammatory etiology[35-37]. The findings suggest that vitamin D supplementation may have beneficial effects on the outcomes of critically ill patients experiencing respiratory deficiency. So, these highlight the potential importance of vitamin D in managing such patients and warrant further investigation into its role in improving clinical outcomes in critical care settings.\u003c/p\u003e\n\u003cp\u003eConsistent with our findings, Singh et al. conducted a systematic review that illustrates the association between Vitamin D supplementation and a reduction in both the duration of stay in the intensive care unit for critically ill patients[24]. However their research encompassed patients with a range of medical conditions necessitating ICU-level support, including those suffering from sepsis or septic shock, individuals in need of neurocritical care, and patients solely diagnosed with ventilator-associated pneumonia. \u0026nbsp;In a randomized, double-blind, placebo-controlled, single-center trial(The VITdAL-ICU Randomized Clinical Trial) conducted by Amrein et al., compared with the placebo, supplementation with high-dose of vitamin D3(540,000 IU followed by monthly\u0026nbsp;maintenance doses of 90,000 IU for 5 months) could not decline the length of hospital stay, in-hospital mortality, or 6-month mortality[29]\u0026nbsp;that is same of our finding. However, there are some differences, including the study population (medical and surgical ICU patients) and the bolus dosage of vitamin D supplementation, rather than continuous administration. Similar to our findings, Hu et al. conducted a retrospective cohort study, suggesting that vitamin D supplementation in ARF patients may decrease in-hospital and ICU mortality rates\u0026nbsp;[27]. Despite having a larger sample size compared to our trial, their study lacks obviousness regarding the specific type, dosage, and duration of vitamin D supplementation used, as well as the underlying diseases responsible for ARF. \u0026nbsp;This ambiguity raises concerns about the reliability and comparability of their results. In line with our findings, Han et al. showed that supplementation with vitamin D (100,000 IU vitamin D\u003csub\u003e3\u003c/sub\u003e for five days) in mechanically-ventilated critically ill adult patients potentially ameliorates the oxidative stress that was assessed through glutathione disulfide concentration[38].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn relation to vitamin C, previous studies have shown that vitamin C levels in patients admitted to the ICU were significantly lower than those in the control group. Moreover, a notable decline in vitamin C levels was observed during the patients' stay in the ICU[16, 39, 40]. While enteral supplementation with vitamin C did not normalize plasma levels, high-dose intravenous supplementation effectively achieved normal levels and above[17, 41-43]. Research on vitamin C supplementation in critically ill patients has yielded inconsistent findings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFowler et al. conducted a study investigating the effects of intravenous vitamin C infusion (50 mg/kg in dextrose 5%\u0026nbsp;every 6 hours for 96 hours) on organ failure scores and biological markers related to inflammation, particularly CRP levels, and vascular injury, as indicated by thrombomodulin levels, in patients diagnosed with sepsis and acute respiratory distress syndrome (ARDS). Their findings, in contrast to ours, suggested that a 96-hour administration of vitamin C did not result in statistically significant improvements in organ dysfunction scores or the modulation of inflammatory markers and indicators of vascular injury compared to placebo control[44]. However, compared to our study, the duration of vitamin C administration was lower, and the patient groups differed. It’s also worth mentioning that not assessing additional relevant markers leaves gaps in the analysis, which might make it harder to draw solid conclusions. To truly grasp the full picture, a more comprehensive evaluation that examines a broader range of markers would be extremely helpful.\u003c/p\u003e\n\u003cp\u003eConcurrent with these findings in 2018, Zhang et al. conducted a systematic review encompassing five studies involving 142 critically ill patients (trauma, burn, surgical and medical ICU). Their analysis indicated that intravenous vitamin C had vasopressor-sparing effects and diminished the necessity for mechanical ventilation. However, it did not significantly affect overall mortality rates[19].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMahmoodpoor et al. studied high doses of vitamin C (60 mg/kg/day via continuous infusion) in critically ill pneumonia patients, finding reduced inflammation, shorter mechanical ventilation duration, and lower vasopressor use, but no significant effect on mortality rates[17].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCritically ill patients in the catabolic phase experience oxidative stress, hyperinflammation, mitochondrial dysfunction, and cellular immune dysfunction. These conditions result in an increased demand for micronutrients and trace elements with antioxidant and anti-inflammatory properties compared to individuals in good health. Conversely, micronutrient deficiencies are prevalent among critically ill patients, primarily due to heightened metabolic demands associated with underlying conditions, reduced nutritional intake, treatments in the ICU, medications, and prior malnutrition. Consequently, the supplementation of micronutrients holds promise for enhancing organ function and improving clinical outcomes, given their roles in various biological pathways and enzymatic processes. It is important to note that our ineffective results in improving clinical outcomes may be influenced by an insufficient sample size, which was determined based on changes in IL-6 levels and was inadequate to demonstrate changes in clinical outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths and Limitations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary strength of this study lies in evaluating two markers for inflammation and oxidative stress along with clinical outcomes, so this methodology enables a more comprehensive interpretation. In addition, the blinding of oral vitamin D and intravenous vitamin between the two groups is another strength of this trial. However, despite this strength, our trial faced several limitations. One notable limitation is the sample size, which was determined to assess IL-6 as the primary outcome between the intervention and control groups due to the deprivation of financial resources. Consequently, the sample size is insufficient for detecting differences in the clinical outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAccording to our findings, daily Supplementation with 5,000 IU of vitamin D drops and 2,000 mg intravenous vitamin C in critically ill ARF patients for 10 days could decrease inflammation markers, oxidative stress indices, and the duration of ICU stay but did not affect the length of mechanical ventilation, hospital stay, or mortality. Therefore, future trials with larger sizes that could reach sufficient levels for evaluating clinical outcomes are necessary.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e25(OH)D: 25-hydroxyvitamin D\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ARDS: Acute Respiratory Distress Syndrome\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ARF: Acute respiratory failure\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;APACHE II: Acute Physiology and Chronic Health Evaluation II\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;COPD: Chronic Obstructive Pulmonary Disease\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ELISA: \u0026nbsp;Enzyme-Linked Immunosorbent Assay\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IBW: Ideal Body Weight\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ICU: Intensive Care Unit\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IFD: ICU Free Days\u003c/p\u003e\n\u003cp\u003eHFD: Hospital Free Days\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;HPLC: high-performance liquid chromatography\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IL-6: Interleukin-6\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;hs-CRP: High-sensitivity C-reactive protein\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MDA: Malondialdehyde\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MFD: \u0026nbsp; Mechanical Ventilation-Free Days\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;NUTRIC: \u0026nbsp;Nutrition Risk in Critically Ill\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;TAC: Total Antioxidant Capacity\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRCT: Randomized Controlled Trial\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SOFA: Sequential Organ Failure Assessment\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors express gratitude to all the study participants, the respiratory ICU staff of Firoozgar Hospital, and others who helped us conduct this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed equally to the study concept and design, acquisition of subjects and/or data, analysis and interpretation of data, and manuscript preparation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is funded by the Iran University of Medical Sciences, Tehran, Iran (grant no:\u0026nbsp;1402-2-2-26371).\u0026nbsp;The funders have no role in the design of the trial, procedures, intervention, collection, evaluation, and data analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was obtained from the Committee of Iran University of Medical Sciences (IR.IUMS.REC.1402.210). Before participating in the research project, all participants must provide and sign a written informed consent form detailing the terms and conditions. Upon signing the consent form, participants will be required to indicate their consent for utilizing their data in the event of withdrawal. Furthermore, researchers will seek participants\u0026apos; authorization to share pertinent data with individuals affiliated with the participating universities or regulatory authorities. It is important to note that biological specimens will not be gathered for storage purposes in this trial. The study has been registered at https://irct.behdasht.gov.ir/. Number: IRCT20090822002365N29\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publication\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors approved the final version of the manuscript and agreed to all aspects of the work being published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1.Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran\u003c/p\u003e\n\u003cp\u003e2. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Department of Internal Medicine, School of Medicine, Firoozgar General Hospital, Iran University of Medical Sciences (IUMS), Tehran, Iran.\u003c/p\u003e\n\u003cp\u003e3. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Firoozgar Clinical Research Development Centre (FCRDC), Iran University of Medical Sciences (IUMS), Tehran, Iran.\u003c/p\u003e\n\u003cp\u003e4. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Department of Clinical Nutrition and Dietetics, National Nutrition and Food Technology Research Institute, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran\u003c/p\u003e\n\u003cp\u003e5. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Department of Statistics and Epidemiology, School of Public Health, Tabriz University of Medical Sciences, Tabriz, Iran\u003c/p\u003e\n\u003cp\u003e6. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Department of Pediatric Nursing, School of Nursing and Midwifery, Iran Medical Sciences University, Tehran, Iran\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eScala R, Heunks L. Highlights in acute respiratory failure. Eur Respir Rev, 2018. 27(147).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVillgran VD, et al. Acute Respiratory Failure. Crit Care Nurs Q. 2022;45(3):233\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang P, Esper AM. Acute Respiratory Failure: Problems Solved and Unsolved. Crit Care Clin. 2024;40(2):xiii\u0026ndash;xv.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen L, Rackley CR. Diagnosis and Epidemiology of Acute Respiratory Failure. Crit Care Clin. 2024;40(2):221\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFranca SA, et al. The epidemiology of acute respiratory failure in hospitalized patients: a Brazilian prospective cohort study. J Crit Care. 2011;26(3):e3301\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLavender Z, Sandor P, Ricker MA. Breathe In, Breathe Out: Respiratory Considerations in the Intensive Care Unit. Physician Assistant Clin. 2019;4(2):361\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLing RR, et al. Epidemiology of acute hypoxaemic respiratory failure in Australian and New Zealand intensive care units during 2005\u0026ndash;2022. A binational, registry-based study. Intensive Care Med. 2024;50(11):1861\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbebe KG, Koster Y, Bimrew M. Prevalence of Respiratory Failure And Associated Factors In Adult Intensive Care Unit of Saint Paul\u0026rsquo;s And Addis Ababa Burn, Emergency And Trauma Hospital, Ethiopia 2020. 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePe\u0026ntilde;a-L\u0026oacute;pez Y, et al. Limiting ventilator-associated complications in ICU intubated subjects: strategies to prevent ventilator-associated events and improve outcomes. Expert Rev Respir Med. 2018;12(12):1037\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNi YN, et al. The effect of hyperoxia on mortality in critically ill patients: a systematic review and meta analysis. BMC Pulm Med. 2019;19(1):53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaribhai S, Mahboobi SK. Ventilator Complications, in StatPearls. 2024, StatPearls Publishing Copyright \u0026copy; 2024, StatPearls Publishing LLC.: Treasure Island (FL).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRen J, et al. Association of lactate/albumin ratio with in-hospital mortality in ICU patients with acute respiratory failure: A retrospective analysis based on MIMIC-IV database. Med (Baltim). 2023;102(39):e35410.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColgan SP, Campbell EL, Kominsky DJ. Hypoxia and Mucosal Inflammation. Annu Rev Pathol. 2016;11:77\u0026ndash;100.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCasaer MP, Bellomo R. Micronutrient deficiency in critical illness: an invisible foe? Intensive Care Med. 2019;45(8):1136\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCutuli SL et al. Vitamin D Status and Potential Therapeutic Options in Critically Ill Patients: A Narrative Review of the Clinical Evidence. Diagnostics (Basel), 2022. 12(11).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoekkoek WAC, et al. Micronutrient deficiencies in critical illness. Clin Nutr. 2021;40(6):3780\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahmoodpoor A, et al. Effect of Vitamin C on mortality of critically ill patients with severe pneumonia in intensive care unit: a preliminary study. BMC Infect Dis. 2021;21(1):616.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeng H, et al. Randomised trials of vitamin D(3) for critically ill patients in adults: systematic review and meta-analysis with trial sequential analysis. Intensive Care Med. 2017;43(2):277\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang M, Jativa DF. Vitamin C supplementation in the critically ill: A systematic review and meta-analysis. SAGE Open Med. 2018;6:2050312118807615.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eP LL, Lamontagne F. Vitamin C for the critically ill: Is the evidence strong enough? Nutrition. 2019;60:185\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmrein K, Christopher KB, McNally JD. Understanding vitamin D deficiency in intensive care patients. Intensive Care Med. 2015;41(11):1961\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmrein K, Oudemans-van HM, Straaten, Berger MM. Vitamin therapy in critically ill patients: focus on thiamine, vitamin C, and vitamin D. Intensive Care Med. 2018;44(11):1940\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLanglois PL, D'Aragon F, Manzanares W. Vitamin D in the ICU: More sun for critically ill adult patients? Nutrition. 2019;61:173\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh S, et al. Vitamin D Supplementation in Critically Ill Patients: A Meta-Analysis of Randomized Controlled Trials. Cureus. 2022;14(4):e24625.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarpagnano GE, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest. 2021;44(4):765\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThickett DR, et al. Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients: a retrospective cohort study. BMJ Open Respir Res. 2015;2(1):e000074.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu S, et al. Vitamin D supplementation is beneficial in improving the prognosis of patients with acute respiratory failure in the intensive care unit: a retrospective study based on the MIMIC-IV database. Front Med (Lausanne). 2023;10:1271060.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDastan F, et al. Effects of High-Dose Vitamin D Replacement on the Serum Levels of Systemic Inflammatory Biomarkers in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Copd. 2019;16(3\u0026ndash;4):278\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmrein K, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312(15):1520\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilliams S, Heuberger R. Outcomes of Vitamin D Supplementation in Adults Who are Deficient and Critically Ill: A Review of the Literature. Am J Ther, 2016. 23(6): pp. e1890-e1902.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi Y, Ding S. Serum 25-Hydroxyvitamin D and the risk of mortality in adult patients with Sepsis: a meta-analysis. BMC Infect Dis. 2020;20(1):189.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBraun AB, et al. Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill. Crit Care Med. 2012;40(12):3170\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRimaniol JM, Authier FJ, Chariot P. Muscle weakness in intensive care patients: initial manifestation of vitamin D deficiency. Intensive Care Med. 1994;20(8):591\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHendryx M, Luo J. A test of vitamin D benefits on respiratory health mediated through inflammatory markers. Chron Respir Dis. 2015;12(1):24\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHamza FN et al. Immunomodulatory Properties of Vitamin D in the Intestinal and Respiratory Systems. Nutrients, 2023. 15(7).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHansdottir S, Monick MM. Vitamin D effects on lung immunity and respiratory diseases. Vitam Horm. 2011;86:217\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHerr C, et al. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer. Respir Res. 2011;12(1):31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan JE, et al. Oxidative stress in critically ill ventilated adults: effects of vitamin D(3) and associations with alveolar macrophage function. Eur J Clin Nutr. 2018;72(5):744\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarr AC, et al. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. 2017;21(1):300.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerger MM. Vitamin C requirements in parenteral nutrition. Gastroenterology. 2009;137(5 Suppl):S70\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Zanten AR, et al. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. JAMA. 2014;312(5):514\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFowler AA 3, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLong CL, et al. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res. 2003;109(2):144\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFowler AA 3rd, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019;322(13):1261\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nutrition-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nutj","sideBox":"Learn more about [Nutrition Journal](http://nutritionj.biomedcentral.com/)","snPcode":"12937","submissionUrl":"https://submission.nature.com/new-submission/12937/3","title":"Nutrition Journal","twitterHandle":"@NutrJournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Acute respiratory failure, Vitamin C, Vitamin D, Inflammation, Oxidative stress","lastPublishedDoi":"10.21203/rs.3.rs-6683114/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6683114/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAcute respiratory failure (ARF) is the most common organ failure, affecting up to 30% of all intensive care unit (ICU) admissions. Since vitamin deficiencies are frequent in critically ill patients, and considering that the two primary mechanisms involved in ARF are inflammation and oxidative stress, this study aims to investigate the effects of co-supplementation of vitamins D and C on inflammatory parameters, oxidative stress, and clinical outcomes in critically ill ARF patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this double-blind, randomized, placebo-controlled trial, ARF patients admitted to the ICU were randomly assigned to either the intervention group (daily 2000 mg of intravenous vitamin C plus 5000 IU of oral vitamin D) or the control group (placebo). The intervention lasted 10 days, and patients were followed for 90 days, assessing inflammation, oxidative stress parameters, and clinical outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThirty-four patients in the intervention group and 33 in the control group completed the trial. At the end of the intervention, High-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and malondialdehyde (MDA) were significantly reduced, while total antioxidant capacity (TAC) increased significantly in the intervention group compared to both the baseline and the control group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Among the clinical outcomes, only the duration of ICU stay was shorter in the intervention group (0.028). However, 90-day survival (HR 0.55; 95% CI 0.21\u0026ndash;1.41; P\u0026thinsp;=\u0026thinsp;0.22) did not show a significant difference between the two groups.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur study concluded that vitamin D and C supplementation may improve inflammation and oxidative status in critically ill ARF patients, reducing ICU stays but not affecting 90-day mortality.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eThe study has been registered at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://irct.behdasht.gov.ir/\u003c/span\u003e\u003cspan address=\"https://irct.behdasht.gov.ir/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Number: IRCT20090822002365N29.Registered on 2023-08-05 and it was ethically approved by the Committee of Iran University of Medical Sciences (registration IR.IUMS.REC.1402.210).\u003c/p\u003e","manuscriptTitle":"Clinical randomized trial of vitamin D and C supplementation in critically ill patients with respiratory failure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-04 08:54:54","doi":"10.21203/rs.3.rs-6683114/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-18T15:07:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-18T01:01:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-14T10:50:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"11945295676500205820944951843781198988","date":"2025-06-10T12:04:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"130142382069083895323364111084304577896","date":"2025-05-29T14:10:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-29T14:04:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-28T18:51:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-20T01:53:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Nutrition Journal","date":"2025-05-16T19:18:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nutrition-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nutj","sideBox":"Learn more about [Nutrition Journal](http://nutritionj.biomedcentral.com/)","snPcode":"12937","submissionUrl":"https://submission.nature.com/new-submission/12937/3","title":"Nutrition Journal","twitterHandle":"@NutrJournal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"350cb379-fad3-4bdd-a563-ea1a1437bad8","owner":[],"postedDate":"June 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-06T16:00:24+00:00","versionOfRecord":{"articleIdentity":"rs-6683114","link":"https://doi.org/10.1186/s12937-025-01214-5","journal":{"identity":"nutrition-journal","isVorOnly":false,"title":"Nutrition Journal"},"publishedOn":"2025-09-29 15:56:51","publishedOnDateReadable":"September 29th, 2025"},"versionCreatedAt":"2025-06-04 08:54:54","video":"","vorDoi":"10.1186/s12937-025-01214-5","vorDoiUrl":"https://doi.org/10.1186/s12937-025-01214-5","workflowStages":[]},"version":"v1","identity":"rs-6683114","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6683114","identity":"rs-6683114","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}