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Original Investigation
August 18, 2020

Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial

Author Affiliations
  • 1Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 2Center for Resuscitation Science, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 3Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 4Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 5Division of Emergency Critical Care Medicine, Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 6Department of Emergency Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York
  • 7Department of Emergency Medicine, McGovern Medical School at UTHealth, Houston, Texas
  • 8Division of Critical Care, Department of Internal Medicine, McGovern Medical School at UTHealth, Houston, Texas
  • 9Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 10Research Center for Emergency Medicine, Aarhus University Hospital, Aarhus, Denmark
  • 11Prehospital Emergency Medical Services, Central Denmark Region, Denmark
  • 12Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 13Sinai Grace Hospital, Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, Michigan
  • 14Division of Critical Care, Department of Anesthesia Critical Care, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 15Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mount Auburn Hospital, Cambridge, Massachusetts
  • 16Division of Critical Care Medicine, South Shore Hospital, Weymouth, Massachusetts
  • 17Division of Pulmonary, Critical Care, and Sleep Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York
  • 18Beaumont Hospital, Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Beaumont, Michigan
  • 19Division of Pulmonary and Critical Care Medicine, Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Michigan
  • 20Department of Critical Care Medicine, Mayo Clinic, Phoenix, Arizona
JAMA. 2020;324(7):642-650. doi:10.1001/jama.2020.11946
Visual Abstract. Ascorbic Acid, Corticosteroids, and Thiamine for Organ Protection in Septic Shock
Ascorbic Acid, Corticosteroids, and Thiamine for Organ Protection in Septic Shock
Key Points

Question  What is the effect of the combination of ascorbic acid, corticosteroids, and thiamine on the trajectory of organ injury in septic shock?

Findings  In this randomized clinical trial that included 200 adults with septic shock, treatment for 4 days with a combination of parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) vs placebo every 6 hours resulted in a change in the Sequential Organ Failure Assessment score of 4.7 in the intervention group vs 4.1 in the placebo group over 72 hours, a difference that was not statistically significant.

Meaning  This trial does not support the routine use of the combination of ascorbic acid, corticosteroids, and thiamine for organ protection in septic shock populations.

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

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