Ari Moskowitz1,2, David T Huang3,4, Peter C Hou5, Jonathan Gong6, Pratik B Doshi7,8, Anne V Grossestreuer2,9, Lars W Andersen2,10,11, Long Ngo12, Robert L Sherwin13, Katherine M Berg1,2, Maureen Chase2,9, Michael N Cocchi2,14, Jessica B McCannon15, Mark Hershey16, Ayelet Hilewitz17, Maksim Korotun17, Lance B Becker6, Ronny M Otero18, Junior Uduman19, Ayan Sen20, Michael W Donnino1,2,9. 1. Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 2. Center for Resuscitation Science, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 3. Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. 4. Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. 5. Division of Emergency Critical Care Medicine, Department of Emergency Medicine, Brigham and Women's Hospital, Boston, Massachusetts. 6. Department of Emergency Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York. 7. Department of Emergency Medicine, McGovern Medical School at UTHealth, Houston, Texas. 8. Division of Critical Care, Department of Internal Medicine, McGovern Medical School at UTHealth, Houston, Texas. 9. Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 10. Research Center for Emergency Medicine, Aarhus University Hospital, Aarhus, Denmark. 11. Prehospital Emergency Medical Services, Central Denmark Region, Denmark. 12. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 13. Sinai Grace Hospital, Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, Michigan. 14. Division of Critical Care, Department of Anesthesia Critical Care, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 15. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mount Auburn Hospital, Cambridge, Massachusetts. 16. Division of Critical Care Medicine, South Shore Hospital, Weymouth, Massachusetts. 17. Division of Pulmonary, Critical Care, and Sleep Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York. 18. Beaumont Hospital, Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Beaumont, Michigan. 19. Division of Pulmonary and Critical Care Medicine, Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Michigan. 20. Department of Critical Care Medicine, Mayo Clinic, Phoenix, Arizona.
Abstract
IMPORTANCE: The combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock. OBJECTIVE: To determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: Randomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019. INTERVENTIONS: Patients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102). MAIN OUTCOMES AND MEASURES: The primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses. RESULTS: Among 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively). CONCLUSIONS AND RELEVANCE: In patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03389555.
IMPORTANCE: The combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock. OBJECTIVE: To determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: Randomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019. INTERVENTIONS: Patients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102). MAIN OUTCOMES AND MEASURES: The primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses. RESULTS: Among 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively). CONCLUSIONS AND RELEVANCE: In patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03389555.
Authors: Michael W Donnino; Lars W Andersen; Maureen Chase; Katherine M Berg; Mark Tidswell; Tyler Giberson; Richard Wolfe; Ari Moskowitz; Howard Smithline; Long Ngo; Michael N Cocchi Journal: Crit Care Med Date: 2016-02 Impact factor: 7.598
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