Discussion
CAP, deaths, death
RECRUITMENT, HYPOVITAMINOSIS, RECRUITMENT, PATHOPHYSIOLOGY, SECONDARY
The study was designed and powered as a feasibility study of supplemental vitamin C in moderate to severe CAP and provided some important insights on recruitment, acceptability, and clinical outcomes that will help design future studies.Recruitment of patients was feasible as the percentage enrolled (27%) was similar to that expected (25%) but the recruitments rates were lower than expected (62 vs > 100 per year). This was attributable to several factors. The study was done during the COVID pandemic when there were strict lockdown periods in New Zealand. That resulted in major reductions in transmission of both COVID-19 and other respiratory pathogensThere was a high rate of acceptability, administration and delivery of the intravenous agents but there was a delay between admission and administration of the first dose of vitamin C (median 22 h) shortening the course of parenteral therapy. Ideally, adjunctive vitamin C should be administered concurrently with the antimicrobial therapy by randomising and treating patients in the emergency department. This would reduce the nadir of vitamin C concentration, replenish stores more quickly, and maximise any potential benefit of the vitamin C. The time course of action of vitamin C is not known but given the multiple metabolic benefits, this may be quite short. Seven intravenous doses were missed overall. Most of these occurred when subjects were transferred between the acute admission ward and the general medical wards or ICU. This problem was promptly eliminated once it was recognised. After discharge, patients self-administered the oral medication and 88% reported completing their course of treatment. The dose of vitamin C administered produced a rapid rise in the peripheral blood concentrations and these were about 12-fold higher in the treatment group compared with controls after one day and over three-fold higher than saturating levels (> 70 µmol/L), whereas the median concentration remained in the hypovitaminosis range in the placebo groupWe did not identify a difference in our primary or secondary outcome measure between the groups. However, our study was not powered to show such differences and a benefit cannot be ruled out. The consistent signal towards a benefit from vitamin C across the measures including mortality, clinical stability, and length of hospital stay indicates that a definitive trial is warranted. The mortality in the control group of 5% (95% CI 1.4–17%) was lower than expected although still consistent with results from large multicentre data sets. Reports of case fatality ratios for CURB-65 score 2 of 9.2%, and CURB-65 > 2 of 22.3% give an estimated case fatality ratio in moderate/severe CAP of 16%Despite the low mortality there were fewer deaths in the vitamin C treatment group than the control group. This is a similar finding to that of Hunt et alThe endpoint for future trials needs careful consideration. All-cause mortality at 30 days death is a secure endpoint but would require a large multicentre studyThe strength of this study has been the rigorous design and pragmatic execution within routine practice. Our study includes patients with less severe CAP who may benefit from vitamin C administration early in the clinical course when the pathophysiology is more reversable. Limitations include number of severe cases included, exclusion of those unable to consent, and the time to administer the first dose of intravenous vitamin C. The follow up data was limited by using self-reporting of adherence to study medication.We conclude that dosing of vitamin C at 2.5 g IV Q8H followed by 1 g PO thrice daily was safe and well tolerated. The rise in vitamin C was saturating, and sufficient to achieve any expected benefits. Recruitment for a definitive trial would be feasible in a multi-centre study but would require approximately 930 participants to determine any effect on mortality, or 200 participants for a composite end-point.