Tomoko Fujii1,2, Nora Luethi1,3, Paul J Young4,5, Daniel R Frei6, Glenn M Eastwood1,7, Craig J French1,8,9, Adam M Deane10, Yahya Shehabi11,12, Ludhmila A Hajjar13, Gisele Oliveira13, Andrew A Udy1,14, Neil Orford1,15,16, Samantha J Edney4, Anna L Hunt4, Harriet L Judd4, Laurent Bitker7,17, Luca Cioccari1,7,18, Thummaporn Naorungroj7,19, Fumitaka Yanase1,7, Samantha Bates8, Forbes McGain8, Elizabeth P Hudson20, Wisam Al-Bassam11, Dhiraj Bhatia Dwivedi11, Chloe Peppin11, Phoebe McCracken14, Judit Orosz14, Michael Bailey1,9, Rinaldo Bellomo1,7,9. 1. Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. 2. Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine, Kyoto, Japan. 3. Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. 4. Intensive Care Unit, Wellington Hospital, Capital and Coast District Health Board, Wellington, New Zealand. 5. Medical Research Institute of New Zealand, Wellington, New Zealand. 6. Department of Anaesthesia and Pain Medicine, Wellington Hospital, Capital and Coast District Health Board, Wellington, New Zealand. 7. Intensive Care Unit, Austin Hospital, Heidelberg, Victoria, Australia. 8. Department of Intensive Care, Anaesthesia, Pain, and Perioperative Medicine, Footscray Hospital, Western Health, Footscray, Melbourne, Victoria, Australia. 9. University of Melbourne, Parkville, Victoria, Australia. 10. Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Australia. 11. Critical Care and Perioperative Services, School of Clinical Sciences, Monash University and Monash Health, Melbourne, Victoria, Australia. 12. Clinical School of Medicine, University of New South Wales, Sydney, Australia. 13. Cancer Institute of the State of Sao Paulo, Sao Paulo, Brazil. 14. Department of Intensive Care and Hyperbaric Medicine, Alfred Hospital, Melbourne, Victoria, Australia. 15. Intensive Care Unit, University Hospital Geelong, Barwon Health, Geelong, Victoria, Australia. 16. School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia. 17. Service de médecine intensive et réanimation, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France. 18. Department of Intensive Care Medicine, University Hospital, University of Bern, Bern, Switzerland. 19. Department of Intensive Care, Siriraj Hospital, Mahidol University, Bangkok, Thailand. 20. Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.
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.
RCT Entities:
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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