1609 Original Article Beneficial aspects of high dose intravenous vitamin C on patients with COVID-19 pneumonia in severe condition: a retrospective case series study Bing Zhao1#, Yun Ling2#, Jian Li3#, Yibing Peng4, Jun Huang5, Yihui Wang1, Hongping Qu6, Yuan Gao7, Yingchuan Li8, Bijie Hu9, Shuihua Lu10, Hongzhou Lu2, Wenhong Zhang11, Enqiang Mao1 1Emergency Department of Ruijin Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; 2Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai, China; 3Clinical Research Center in Ruijin Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; 4Department of Laboratory Medicine, Ruijin Hospital, School of Medicine Shanghai Jiaotong University, Shanghai, China; 5Shanghai Institute of Hypertension, Shanghai, China; 6Department of Critical Care Medicine, Ruijin Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China; 7Department of Critical Care Medicine, Renji Hospital, School of Medicine Shanghai Jiaotong University, Shanghai, China; 8Department of Critical Care Medicine, the Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China; 9Department of Infectious Disease, Zhongshan Hospital, Fudan University, Shanghai, China; 10Tuberculosis Department of Shanghai Public Health Clinical Center, Shanghai, China; 11Department of Infectious disease of Shanghai Huashan Hospital, Fudan University, Shanghai, China Contributions: (I) Conception and design: B Zhao, W Zhang, E Mao; (II) Administrative support: W Zhang, E Mao; (III) Provision of study materials or patients: J Huang, Y Peng, Y Wang, H Qu, Y Gao, Y Li, B Hu, S Lu, H Lu; (IV) Collection and assembly of data: Y Ling, J Li, J Huang, Y Peng, Y Wang, H Qu, Y Gao, Y Li, B Hu, S Lu, H Lu; (V) Data analysis and interpretation: Y Ling, J Li; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Enqiang Mao. Emergency Department of Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Ruijin 2nd Road 197, Shanghai, China. Email: [email protected]; Wenhong Zhang. Department of Infectious Disease of Shanghai Huashan Hospital, Fudan University, Huashan Road 433, Shanghai, China. Email: [email protected]. Background: Coronavirus disease 2019 (COVID-19) is a global public health event without specific therapeutic agents till now. We aim to determine if high dose intravenous vitamin C (HDIVC) was effective for COVID-19 patients in severe condition. Methods: COVID-19 patients admitted in Shanghai Public Health Clinical Center from January 22, 2020 to April 11, 2020 were retrospectively scrolled. The enrolled patients were those with confirmed diagnosis of severe or critical COVID-19 pneumonia, who received HDIVC within 24 hours after disease aggravation. Main clinical outcomes obtained from 3–5 days (day 3) and 7–10 days (day 7) after HDIVC were compared to the ones just before (day 0) HDIVC. Results: Totally, twelve patients were enrolled including six severe [age of mean, 56; interquartile range (IQR), 32–65 years, 3 men] and six critical (age of mean, 63; IQR, 60–82 years, 4 men) patients. The dosage of vitamin C [median (IQR), mg/kg (body weight)/day] were 162.7 (71.1–328.6) for severe and 178.6 (133.3–350.6) for critical patients. By Generalized estimating equation (GEE) model, C-reactive protein (CRP) was found to decrease significantly from day 0 to 3 and 7 (severe: 59.01±37.9, 12.36±22.12, 8.95± 20.4 mg/L; critical: 92.5±41.21, 33.9±30.2, 59.56±41.4 mg/L). Lymphocyte and CD4+ T cell counts in severe patients reached to normal level since day 3. Similar improving trends were observed for PaO2/FiO2 (severe: 209.3±111.7, 313.4±146, 423.3±140.8; critical: 119.9±52.7, 201.8±86.64, 190.5±51.99) and sequential organ failure assessment score (severe: 2.83±1.72, 1.33±1.63, 0.67±1.03; critical: 6.67±2.34, 4.17±2.32, 3.83±2.56). Better improving effect was observed in severe than critical patients after HDIVC. Conclusions: HDIVC might be beneficial in aspects of inflammatory response, immune and organ function for aggravation of COVID-19 patients. Further clinical trials are in warrant. Trial registration: This trial has been retrospectively registered in Chinese Clinical Trail Registry (ChiCTR2000032716) on May 8, 2020. http://www.chictr.org.cn/showproj.aspx?proj=53389. © Annals of Palliative Medicine. All rights reserved. Ann Palliat Med 2021;10(2):1599-1609 | http://dx.doi.org/10.21037/apm-20-1387 1600 Zhao et al. HDIVC for COVID-19 in aggravation Keywords: Coronavirus disease 2019 (COVID-19); vitamin C; aggravation; therapy; C-reactive protein (CRP) Submitted Jul 09, 2020. Accepted for publication Sep 28, 2020. doi: 10.21037/apm-20-1387 View this article at: http://dx.doi.org/10.21037/apm-20-1387 Introduction a cohort of septic patients with ARDS. (II) Its immune enhancing property and the potential anti-virus ability (11), Coronavirus disease 2019 (COVID-19), the infectious which might help for improving lymphopenia, the main illness caused by severe acute respiratory coronavirus 2 characteristic of COVID-19 which was related with (SARS-CoV-2) has become a worldwide heath care crisis severity (12). Also, application of HDIVC in COVID-19 since December 2019 (1,2). The severity of COVID-19 has already got concerns of some scholars (13). Still, is classified into mild, moderate, severe and critical type promotion of HDIVC needs further evidence. on the guideline made by National Health and Family In this retrospective case series study, we made an Planning Commission of the People’s Republic of China (3). observational comparison of outcomes before and after The severe patient is mainly characterized with deteriorated HDIVC in a cohort of severe and critical patients after respiratory function and rapid progression of radiological disease aggravation occurred. The dosage of vitamin lesions, and the critical patient further requires mechanical C [median (IQR)] applied in severe patients was 162.7 ventilation (MV), accompanying with shock or multiple (71.1–328.6) mg/kg (body weight)/day and 178.6 (133.3– organ failure (Table S1). The aged patients and those with 350.6) mg/kg/day in critical patients. The main outcomes pre-existing respiratory, cardiac and diabetic disease appear were mainly divided into inflammatory response, immune to be at high risk of rapid development to severe and critical and organ dysfunction. To the best of our knowledge, type (4). Various methods of respiratory support are the it is the first time to describe the effect of HDIVC on main treatment for the severe and critical patients, especially COVID-19 pneumonia. We present the following article in the situation of disease aggravation. The respiratory according to the STROBE reporting checklist (available at supports are consisted of high flow oxygen therapy, http://dx.doi.org/10.21037/apm-20-1387). noninvasive or invasive MV and extracorporeal membrane oxygenation (ECMO). As effective antiviral therapy is still vacant, the mortality of COVID-19 patients who required Methods MV was reported as high as 66% (5). Therefore, it is Study design and participants important to develop an effective rescue therapy for these patients, especially in the situation of disease aggravation. This study is a retrospective case series study. It was Vitamin C, one of the key antioxidants of the body, conducted in accordance with the amended Declaration has been highlighted recently in the field of critical care of Helsinki (as revised in 2013) and was approved by the medicine (6). High does intravenous vitamin C (HDIVC), institutional ethics board of Ruijin Hospital, Shanghai a new developed method of administration, has been Jiaotong University school of medicine. Oral consents proven to exert beneficial effect in various critical illness were obtained from each enrolled patient. COVID-19 by animal and clinical study (7,8). The rationale for patients admitted in Shanghai public health clinical HDIVC application in the treatment of severe and critical center from January 22, 2020 to April 11, 2020 were COVID-19 patients, as we deemed, relies on (I) its effective retrospectively scrolled. The inclusion criteria were: (I) ability for eliminating the burst of reactive oxygenase age >18 years; (II) patients who was diagnosed with severe species (ROS) and the following cytokine storm (9), which or critical COVID-19 pneumonia. Diagnosis and severity are the basis for acute respiratory distress syndrome (ARDS). classification were based on the guideline made by National The recent CITRIS-ALI study (10) showed HDIVC Health and Family Planning Commission of the People’s (50 mg/kg actual body weight every 6 hours for 96 hours) Republic of China (3) (the specific criteria of severity was reduced 28 day all-cause mortality (29.8% vs. 46.3%) in shown in Table S1). (III) The severe and critical patients © Annals of Palliative Medicine. All rights reserved. Ann Palliat Med 2021;10(2):1599-1609 | http://dx.doi.org/10.21037/apm-20-1387 Annals of Palliative Medicine, Vol 10, No 2 February 2021 1601 suffered with disease aggravation which was defined as All statistical analyses were performed using SAS v. 9.2 (SAS continuous decreasing of PaO2/FiO2 or enlargement of Institute Inc., USA). Two-sided P values of less than 0.05 lung radiological lesion for 1–3 days. (IV) The enrolled were deemed to be statistically significant. patients should accept HDIVC within 24 hours after disease aggravation. The judgement of aggravation occurrence Results and the initiation of HDIVC was performed by Shanghai COVID-19 pneumonia expert group; the dosage of vitamin Patients characteristics C was determined according to the common opinion of A total of twelve COVID-19 patients were enrolled, among expert group based on the previous clinical study and which six of them were classified into severe type, and research work.