January 2021
Jing Zhang, Xin Rao, Yiming Li, Yuan Zhu, Fang Liu, Guangling Guo, Guoshi Luo, Zhongji Meng, Daniel De Backer, Hui Xiang & Zhiyong Peng

 

Abstract

Background

Few specific medications have been proven effective for the treatment of patients with severe coronavirus disease 2019 (COVID-19). Here, we tested whether high-dose vitamin C infusion was effective for severe COVID-19.

 

Methods

This randomized, controlled, clinical trial was performed at 3 hospitals in Hubei, China. Patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the ICU were randomly assigned in as 1:1 ratio to either the high-dose intravenous vitamin C (HDIVC) or the placebo. HDIVC group received 12 g of vitamin C/50 ml every 12 h for 7 days at a rate of 12 ml/hour, and the placebo group received bacteriostatic water for injection in the same way within 48 h of arrival to ICU. The primary outcome was invasive mechanical ventilation-free days in 28 days (IMVFD28). Secondary outcomes were 28-day mortality, organ failure (Sequential Organ Failure Assessment (SOFA) score), and inflammation progression (interleukin-6).

 

Results

Only 56 critical COVID-19 patients were ultimately recruited due to the early control of the outbreak. There was no difference in IMVFD28 between two groups (26.0 [9.0–28.0] in HDIVC vs 22.0 [8.50–28.0] in control, p = 0.57). HDIVC failed to reduce 28-day mortality (P = 0.27). During the 7-day treatment period, patients in the HDIVC group had a steady rise in the PaO2/FiO2 (day 7: 229 vs. 151 mmHg, 95% CI 33 to 122, P = 0.01), which was not observed in the control group. IL-6 in the HDIVC group was lower than that in the control group (19.42 vs. 158.00; 95% CI -301.72 to -29.79; P = 0.04) on day 7.

 

Conclusion

This pilot trial showed that HDIVC failed to improve IMVFD28, but might show a potential signal of benefit in oxygenation for critically ill patients with COVID-19 improving PaO2/FiO2 even though.

 

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a global health issue [1, 2]. While the majority of patients presented with mild symptoms and did not even need hospitalization [3], nearly 30% of adult patients suffer from severe pneumonia and acute respiratory distress syndrome (ARDS), often associated with sepsis or septic shock, and multiple organ (kidney, liver, and heart) failure. Patients with ARDS and systemic complications require critical care and lead to a higher risk of death [4, 5, 6]. Due to the lack of effective medications against SARS-COV-2, the main management is supportive therapy.

Similar to the pathophysiology of severe acute respiratory syndrome (SARS)-related ARDS, SARS-CoV-2 infection stimulates the innate immune system, causing numerous types of cytokine release, namely, a “cytokine storm”, inducing systemic inflammatory response [7, 8] and multiple organ failure [9, 10]. A retrospective study on SARS suggested that the worsening after 2 weeks was not related to uncontrolled viral replication, but related to immunopathological damage [11]. Therefore, antiviral therapy alone may be insufficient to treat COVID-19 patients.

Vitamin C (ascorbic acid, ascorbate) functions as a potent water-soluble antioxidant by directly scavenging oxygen free radicals and acting as an essential co-factor for the production of catecholamines, vasopressin, and cortisol in the human body [12]. Vitamin C is also found in high concentrations in leukocytes and implicated in several immune responses and functions [13]. Emerging evidence in preclinical studies indicated that vitamin C played a crucial role in ameliorating the effects of inflammation by inhibiting proinflammatory cytokine production, assisting immunoregulation, neutralizing reactive oxygen species (ROS), and protecting host cells [14, 15]. Hypovitaminosis C was ubiquitous in critically ill patients, and approximately 40% of the patients had a severe deficiency [16], while the low vitamin C serum level cannot be corrected by oral supplementation due to the issue of pharmacokinetics [17]. In a latest research, of 18 adult ICU patients COVID-19 who met ARDS criteria, 94.4% had undetectable vitamin C levels and 1 patient had low levels [18]. Thus, high-dose intravenous vitamin C (HDIVC) was added to the standard therapy of critically ill patients in recent studies, such as sepsis [19,20,21], ARDS [21, 22], cardiac surgery [23], and burn [24]. The results showed that HDIVC was safe for critically ill patients and significantly reduced vasopressor support [25], limited organ injury [26], shortened the duration of mechanical ventilation [27] and ICU stay [28], and safety/feasibility in severe sepsis [19]. Additionally, vitamin C has direct nonspecific antiviral activity in vitro [29], although it is unclear whether this confers any protection to humans with COVID-19.

Therefore, we hypothesized that HDIVC together with conventional treatments would improve the outcomes for adult patients admitted to the ICU due to severe COVID-19 by preventing cytokine storms and reducing lung and other organ injuries. In this context, we conducted this multicenter, randomized, blind clinical trial to provide a therapeutic strategy for critically ill patients with COVID-19.

 

Methods

This study is a multicenter, randomized trial that was approved by the ethics committee of Zhongnan Hospital of Wuhan University (#2020001). This study was conducted in the ICUs of Zhongnan Hospital of Wuhan University, Leishenshan (Thunder God Mountain) Hospital, and Taihe Hospital from February 14, 2020, to March 29, 2020. The ICUs specifically for COVID-19 from Zhongnan Hospital and Leishenshan Hospital were managed by the same team. The trial was registered on the website of ClinicalTrials.gov (ID: NCT04264533; registered February 14 2020) before patient recruitment.

 

Patient enrollment

Patients were screened and enrolled following admission to the three ICUs. The patients who were diagnosed as severe SARS-CoV-2-related pneumonia, appeared or had a high risk of multiple organs injury would be transferred to ICU. The following inclusion criteria were met: (1) age  ≥ 18 and < 80 years; (2) RT-PCR positive for SARS-CoV-2; (3) pneumonia confirmed by chest imaging and admission to the ICU; (3) PaO2/FiO2(P/F) < 300 mmHg. Exclusion criteria were allergy to vitamin C, pregnancy or breastfeeding, expected survival duration < 24 h, and previous history of glucose-6-phosphate dehydrogenase deficiency or end-stage pulmonary disease. Patients who were already enrolled in other clinical trials were excluded as well. If these criteria were met within 48 h of ICU admission, informed consent was obtained from the patients or their family members. The reason was because the efficacies of the treatments could not be evaluated with limited times of treatment.

 

Randomization, allocation and blinding

Each ICU was assigned with an independent random numeric table generated by Microsoft Excel 2019 by the primary investigator alone. Each table had equal numbers of 1 and 2, which represented the placebo group (bacteriostatic water infusion) and treatment group (HDIVC), respectively. The generated random list was stored by the principal investigator who was not involved in the treatment of patients and hidden to the other investigators. When a patient was transferred to the ICU and met the enrollment criteria, the clinician on duty would inform the principal investigator and obtain a number from the list. Then, participants were enrolled in the corresponding group according to the chronological order of ICU recruitment. The grouping and intervention were unknown to the participants and investigators who were responsible for data collection and statistical analysis. VC injection and sterile water for injection were both colorless and contained in the same brown syringes with different marks and without explanations on the syringe to make sure that patients could not distinguish the treatment they receive.

 

Study interventions

Patients were randomized to receive vitamin C or placebo within 48 h after admission to the ICU. To control the infusion rates accurately and not affect the fluid management of severe patients, we infused vitamin C or placebo via central vein catheterization controlled by a pump. The study groups in this trial were (1) HDIVC: 24 g vitamin C per day. Patients were infused with 12 g vitamin C diluted in 50 ml of bacteriostatic water every 12 h at a rate of 12 ml/hour by infusion pump for 7 days. (2) Placebo: 50 ml of bacteriostatic water infused every 12 h at the same rate. Study interventions were initiated on the same day as informed consent and randomization. The preparation, transportation, storage, and use of therapies (VC and bacteriostatic water for injection) were in line with the drug management protocol in each hospital.

 

General treatments and standard procedure of ventilation supports

In addition, other general treatments followed the latest COVID-19 guidelines [30]. Oseltamivir and azithromycin were usually used in the general ward. After ICU admission, low weight molecular heparin was applied for the prevention deep vein thrombus. Piperacillin/tazobactam was used for patients receiving tracheal intubation.

If the patients showed the symptoms of rapid deterioration of hypoxemia, severe ARDS, or septic shock, hydrocortisone (1 mg/kg/day) could be considered.

Respiratory support (IMV, NIV and HFNC) were given to patients with hypoxic respiratory failure and ARDS. If respiratory failure could not be improved or worsened continuously within a short time after using HFNC or NIV, intubation were performed and the approach of lung-protective ventilation was applied. ECMO was considered as the rescue therapy when the refractory hypoxemia was difficult to be corrected by protective lung ventilation [4]. When patients’ respiratory functions improved and were ready for weaning from the ventilators, the spontaneous breathing test (SBT) was performed. After the SBT was passed, invasive ventilator was considered to remove with the endotracheal tube extubation.

 

Risks and adverse events

Adverse events (AEs) related to HDIVC included (1) nausea or vomiting during or after infusion of VC; (2) electrolyte disturbance; and (3) acute kidney injury, as described by Khoshnam-Rad [31]. AEs and serious adverse events (SAEs) were observed and followed in accordance with the good clinical practice guidelines issued by the National Medical Products Administration of the People’s Republic of China. If any severe adverse events were observed during infusion, the infusion was stopped immediately, and the patient’s vital signs were carefully monitored. All the AEs and SAEs were recorded in detail, and the causal relationship between the infusion and AEs was analyzed.

 

Data collection and management

Baseline data, which included demographics, anthropometrics, comorbid conditions, vital signs, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, and Glasgow Coma Scale (GCS) scores, were obtained on the day of randomization. Laboratory data, Sequential Organ Failure Assessment (SOFA) scores, PaO2/FiO2, and other treatments used were monitored on days 1, 3, and 7 (day 1 was defined as the day of the first administration of study drug).

The primary outcome of the study was invasive mechanical ventilation (IMV)-free days in 28 days (IMVFD28). Secondary outcomes included 28-day mortality, organ functions and inflammatory parameters, including white blood cell counts, neutrophil counts, lymphocyte counts, procalcitonin, interleukin-6 (IL-6), and C-reactive protein (CRP). Multi-organ dysfunction was assessed using SOFA scores. Additionally, vasopressor days, respiratory support days (including invasive and noninvasive mechanical ventilation), IMVFD28, patient condition improvement rate, patient condition deterioration rate, length of ICU and hospital stay, ICU and in-hospital mortality were recorded as additional secondary outcomes of this research. IMVFD28s were defined as the number of days a patient was extubated after recruitment to day 28. If the patient died with MV, a value of zero was assigned. Deterioration of the patient’s condition was defined as the patient requiring HFNC or NIV on day 1 and requiring ECMO or IMV, or dying, after 7 days of treatment. Improvement of the patient’s condition was defined as the patient requiring ECMO or IMV on day 1 and switching to HFNC, NIV, or discharged from the ICU after 7 days of treatment. The P/F was calculated based on the PaO2/FiO2, and we choose the lowest values recorded on the specific day. All the data were collected from the clinical information system of three ICUs. Septic shock was identified according to International Guidelines for Management of Sepsis and Septic Shock (2016). Acute kidney injury was identified according to the Kidney Disease: Improving Global Outcomes definition. Acute cardiac injury was defined as the serum levels of troponin I were above the 99th percentile upper reference limit or new abnormalities were shown in electrocardiography and echocardiography. Acute liver failure (ALF), which is defined as coagulopathy (INR ≥ 1.5), hepatic encephalopathy, and onset less than 26 weeks in a patient without underlying chronic liver disease. Coagulation disorders were defined as the presence of D-dimer > 0.24 mg/L or FDP > 5 mg/L.