Unravelling the paradox of vitamin C research in sepsis

Professor Rinaldo Bellomo’s lasting impact on critical care research stems from his commitment to structured, biologically grounded research programs over isolated studies. His work on vitamin C in sepsis exemplifies this approach. While early enthusiasm grew around combination therapies involving vitamin C, Rinaldo championed a cautious, rigorous, and methodical investigation. He worked closely with collaborators to address key methodological issues, including dosing, stability, and the design of appropriate control groups, which ultimately led to the international VITAMINS trial. This landmark study compared vitamin C, hydrocortisone, and thiamine to hydrocortisone alone in septic shock and found no clinical benefit. Rinaldo embedded a pharmacokinetic substudy to confirm supraphysiological serum vitamin C levels, ensuring biological plausibility of the trial design. Beyond clinical research, he fostered translational research with the Florey Institute using a preclinical sheep model of sepsis. This collaboration uncovered critical mechanisms of septic acute kidney injury and led to the development of mega-dose sodium ascorbate therapy. The program progressed from proof-of-concept to a double-blind pilot randomised trial in septic shock and now underpins a national multicentre phase Ib and II clinical trials. Rinaldo’s legacy is defined by scientific rigour, mentorship, and humility. His visionary, disciplined approach remains a model for impactful research and continues to guide ongoing efforts to advance care for critically ill patients.