Response

Abstract

We thank Drs Shiba, Minami, and Shirashi’s insightful comments and statistical criticisms regarding our trial. However we would like to point out some “small splinters” in their statistical eyes. First, only patients on vasopressors were included in the analysis, clearly shown in the Kaplan-Meier curve as the number at risk.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 (75) Google Scholar We clearly would not include patients not in shock. Second, the Cox proportional hazards analysis that was used to further analyze reversal of shock as an end point is warranted. If patients died while on pressors, their shock did not reverse.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 (75) Google Scholar Cox proportional hazards analysis is the appropriate test in this regard. Third, with all due respect, our study cannot be compared to the VITAMINS (vitamin C, hydrocortisone and thiamine in patients with septic shock) trial because treatment in their trial was started much later.2Fujii T. Luethi N. Young P.J. et al.Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial.JAMA. 2020; 323: 423-431Crossref PubMed Scopus (215) Google Scholar The primary end point was changed before unblinding when we realized we were underpowered for death. Criticism well-taken, however, we feel that cherry picking is a bit harsh because the end point of ascorbic acid improving vasopressor response has been demonstrated in preclinical and clinical studies.3Wilson J.X. Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in endothelium.BioFactors. 2009; 35: 5-13Crossref PubMed Scopus (116) Google Scholar, 4Coloretti I. Biagioni E. Venturelli S. et al.Adjunctive therapy with vitamin C and thiamine in patients treated with steroids for refractory septic shock: a propensity matched before-after, case-control study.J Crit Care. 2020; 59: 37-41Crossref PubMed Scopus (7) Google Scholar, 5Zhang M. Jativa D.F. Vitamin C supplementation in the critically ill: a systematic review and meta-analysis.SAGE Open Med. 2018; 6 (2050312118807615)Crossref PubMed Google Scholar We are not in agreement that adjustment for multiple comparisons in terms of end points is warranted. Steroid therapy was adjusted properly in the control arm; we are not in agreement in terms of adjusting in HAT (ascorbic acid, thiamine, and hydrocortisone) therapy. The authors other statistical insights and recommendations are not useful for most clinicians who treat critically ill septic patients at risk of dying and would not influence the decision whether to employ or not employ HAT therapy clearer. In summary, the ORANGES (outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis) trial demonstrated that HAT therapy reduced time on vasopressors and hence reversal of shock. HAT Therapy: Really Beneficial?CHESTVol. 159Issue 2PreviewIn the ORANGES (outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis) trial that was published in CHEST (July 2020), Iglesias et al1 reported that the combination of IV ascorbic acid, thiamine, and hydrocortisone (HAT) therapy significantly shortened the time to shock reversal in the early treatment of sepsis. We greatly appreciated the authors of the ORANGES trial because it was not only one of the randomized control trials to test the effectiveness of HAT therapy following the VITAMINS (vitamin C, hydrocortisone and thiamine in patients with septic shock) and HYVCTTSSS (hydrocortisone, vitamin C, and thiamine combination treatment for patients with sepsis or septic shock) trials,2,3 but also first-ever double-blinded trial. Full-Text PDF 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