Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial

Chest. 2020 Jul;158(1):164-173. doi: 10.1016/j.chest.2020.02.049. Epub 2020 Mar 17.


Background: Sepsis is a major public health burden resulting in 25% to 30% in-hospital mortality and accounting for over 20 billion dollars of US hospital costs.

Research question: Does hydrocortisone, ascorbic acid, thiamine (HAT) therapy improve clinical outcomes in sepsis and septic shock?

Study design and methods: This was a randomized, double-blinded, placebo-controlled trial conducted from February 2018 to June 2019, assessing an HAT treatment bundle for the management of septic and septic shock patients admitted to an ICU. The primary outcomes were resolution of shock and change in Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes included 28-day mortality, ICU mortality, hospital mortality, procalcitonin clearance (PCT-c), hospital length of stay (LOS), ICU LOS, and ventilator-free days.

Results: One hundred thirty-seven patients were randomized to the treatment group (n = 68) and comparator group (n = 69), respectively, with no significant differences in baseline characteristics. A statistically significant difference was found in the time patients required vasopressors, indicating quicker reversal of shock in the HAT group compared with the comparator group (27 ± 22 vs 53 ± 38 hours, P < .001). No statistically significant change in SOFA score was found between groups 3 (1 - 6) vs 2 (0 - 4), P = .17. No significant differences were found between study arms in ICU and hospital mortality, ICU and hospital LOS, ventilator free days, and PCT-c.

Interpretation: Our 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.

Trial registration: ClinicalTrials.gov; No.: NCT03422159; URL: www.clinicaltrials.gov.

Keywords: HAT therapy; ascorbic acid; hydrocortisone; sepsis; septic shock; thiamine; vitamin c.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Ascorbic Acid / therapeutic use*
  • Critical Care
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Glucocorticoids / therapeutic use*
  • Humans
  • Hydrocortisone / therapeutic use*
  • Male
  • Middle Aged
  • Sepsis / drug therapy*
  • Sepsis / mortality
  • Survival Rate
  • Thiamine / therapeutic use*
  • Vasoconstrictor Agents / therapeutic use
  • Vitamins / therapeutic use*


  • Glucocorticoids
  • Vasoconstrictor Agents
  • Vitamins
  • Ascorbic Acid
  • Hydrocortisone
  • Thiamine

Associated data

  • ClinicalTrials.gov/NCT03422159