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Preliminary Communication
Caring for the Critically Ill Patient
January 17, 2020

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

Author Affiliations
  • 1Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
  • 2Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • 3Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
  • 4Intensive Care Unit, Wellington Hospital, Capital and Coast District Health Board, Wellington, New Zealand
  • 5Medical Research Institute of New Zealand, Wellington, New Zealand
  • 6Department of Anaesthesia and Pain Medicine, Wellington Hospital, Capital and Coast District Health Board, Wellington, New Zealand
  • 7Intensive Care Unit, Austin Hospital, Heidelberg, Victoria, Australia
  • 8Department of Intensive Care, Anaesthesia, Pain, and Perioperative Medicine, Footscray Hospital, Western Health, Footscray, Melbourne, Victoria, Australia
  • 9University of Melbourne, Parkville, Victoria, Australia
  • 10Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Australia
  • 11Critical Care and Perioperative Services, School of Clinical Sciences, Monash University and Monash Health, Melbourne, Victoria, Australia
  • 12Clinical School of Medicine, University of New South Wales, Sydney, Australia
  • 13Cancer Institute of the State of Sao Paulo, Sao Paulo, Brazil
  • 14Department of Intensive Care and Hyperbaric Medicine, Alfred Hospital, Melbourne, Victoria, Australia
  • 15Intensive Care Unit, University Hospital Geelong, Barwon Health, Geelong, Victoria, Australia
  • 16School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
  • 17Service de médecine intensive et réanimation, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France
  • 18Department of Intensive Care Medicine, University Hospital, University of Bern, Bern, Switzerland
  • 19Department of Intensive Care, Siriraj Hospital, Mahidol University, Bangkok, Thailand
  • 20Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia
JAMA. 2020;323(5):423-431. doi:10.1001/jama.2019.22176
Visual Abstract. Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone and Outcomes in Septic Shock
Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone and Outcomes in Septic Shock
Key Points

Question  Does treatment with vitamin C, hydrocortisone, and thiamine lead to a more rapid resolution of septic shock compared with hydrocortisone alone?

Findings  In this randomized clinical trial that included 216 patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days (122.1 hours vs 124.6 hours, respectively).

Meaning  The findings suggest that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.

Abstract

Importance  It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock.

Objective  To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock.

Design, Setting, and Participants  Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019.

Interventions  Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days.

Main Outcomes and Measures  The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality.

Results  Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was –0.6 hours (95% CI, –8.3 to 7.2 hours; P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported.

Conclusions and Relevance  In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.

Trial Registration  ClinicalTrials.gov Identifier: NCT03333278

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