Chest
Volume 158, Issue 1, July 2020, Pages 164-173
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Critical Care: Original Research
Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial

https://doi.org/10.1016/j.chest.2020.02.049Get rights and content

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;

Section snippets

Study Design

This was a randomized, double-blinded, placebo-controlled trial assessing the utilization of an ascorbic acid, thiamine, and hydrocortisone treatment bundle for the management of septic and septic shock patients admitted to an ICU. This study was performed from February 2018 to June 2019 in two community nonteaching hospitals in the United States. The study was approved by the Community Medical Center Institutional Review Board (IRB # 17-004). All participants were provided with written

Study Population

Between February 14th, 2018 and April 29th, 2019, 140 patients consented to participate in the study. Three patients were withdrawn from analysis after randomization because of a new diagnosis of terminal cancer. One hundred thirty-seven patients were randomized. Sixty-eight patients and 69 patients were randomized to the treatment arm (HAT) and comparator arms, respectively (Fig 1). Most of the patients received their first dose of study treatment between 3 and 14 hours (mean, 9.9 ± 4.5 hours)

Discussion

This randomized double-blinded controlled study of HAT therapy demonstrated a marked acceleration in the reversal of shock. This effect remained significant after adjusting for corticosteroid administration in the comparator group, accounting for approximately 15% of the variability observed. This suggests both an independent and synergistic effect of AA in the reversal of shock and in augmenting the hemodynamic effects of corticosteroids.5,21,22 This was in contrast to the recently published

Conclusions

HAT therapy is safe and decreases the duration of shock in patients with sepsis. This effect appears to be due to the ascorbic acid component of HAT therapy rather than the mineralocorticoid effect of steroids alone. Further randomized trials are needed, with larger cohorts to determine whether HAT therapy translates to improved mortality or a decrease in ICU length of stay.

Acknowledgements

Author contributions: All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, including any adverse effects. All authors approved the final version to be published. A. V., J. I., V. P., J. S., Y. E., and J. C. drafted and revised the manuscript. All authors are guarantors of the paper.

Financial/nonfinancial disclosures: None declared.

Other contributions: The authors would like to thank all participants and

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  • Cited by (0)

    FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

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