Response

Abstract

We are very grateful to Garg et al on their insights into why the ORANGES (outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis) trial reduction in duration of vasopressor therapy did translate into improved mortality rates, particularly regarding duration of ascorbic acid therapy.1Iglesias J. Vassallo A.V. Patel V.V. Sullivan J.B. Cavanaugh J. Elbaga Y. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial.Chest. 2020; 158: 164-173Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Due to the pleotropic effects of ascorbic acid, this molecule acts as a stress response factor that is necessary in maintaining homeostasis in physiologic stress states such as sepsis.2Moskowitz A. Andersen L.W. Huang D.T. et al.Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation.Crit Care. 2018; 22: 283Crossref PubMed Scopus (72) Google Scholar Thus, cessation of ascorbic acid therapy too early would be analogous to rapid cessation of corticosteroids rapidly without a taper Garg et al rightly observe that the mortality rate in the ORANGES trial was much lower than the Marik observational control group.1Iglesias J. Vassallo A.V. Patel V.V. Sullivan J.B. Cavanaugh J. Elbaga Y. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial.Chest. 2020; 158: 164-173Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar,3Marik P.E. Khangoora V. Rivera R. Hooper M.H. Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study.Chest. 2017; 151: 1229-1238Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar The strict adherence to sepsis bundle in the ORANGES trial is the most plausible cause at the low mortality rate in this study. The dialytic clearance of ascorbic acid has begun to be appreciated. There is no significant data to support extra supplementation of ascorbic acid in patients receiving high dose (6 g/d) while undergoing continuous renal replacement therapy.4Marik P.E. Hooper M.H. Adjuvant vitamin C in critically ill patients undergoing renal replacement therapy: what’s the right dose?.Crit Care. 2018; 22 (320)Crossref Scopus (6) Google Scholar Patients with sepsis demonstrate a heterogeneous immune response, and further studies should pave the “road ahead” by analyzing transcriptomic to identify patients who may or may be harmed by antiinflammatory therapy such as corticosteroids.5Santhakumaran S. Gordon A. Prevost A.T. O’Kane C. McAuley D.F. Shankar-Hari M. Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS randomised controlled trials.Crit Care. 2019; 23: 156Crossref PubMed Scopus (16) Google Scholar We are in agreement with Garg et al that, to pave the way forward, any studies that involve HAT (ascorbic acid, thiamine, and hydrocortisone) therapy should take into consideration early initiation and optimal duration of therapy. Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES TrialCHESTVol. 158Issue 1PreviewOur results suggest that the combination of IV ascorbic acid, thiamine, and hydrocortisone significantly reduced the time to resolution of shock. Additional studies are needed to confirm these findings and assess any potential mortality benefit from this treatment. Full-Text PDF Vitamin C in Sepsis: The Road AheadCHESTVol. 159Issue 2PreviewWe read with interest the original article by Iglesias et al1 published in CHEST (July 2020) who found a significant reduction in the duration of vasopressor use with hydrocortisone, ascorbic acid (or vitamin C), and thiamine (HAT) therapy in sepsis. This is consistent with the effect of hydrocortisone in the reversal of shock and the proposed benefit of Vitamin C on reducing vasculopathy. Interestingly, this has failed to translate into a mortality benefit. This may have many reasons. The population in the ORANGES (outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis) trial was older, sicker, and had more comorbidities than the populations in previous studies (Table 1). Full-Text PDF