Critical Care, Critical Care Alert

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

Critical Care Alert

Article
Moskowitz A, Huang DT, Hou PC, et al. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock - The ACTS Randomized Clinical Trial. JAMA. 2020;324(7):642-650.

Objective
To determine if the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock.

Background
Efforts to improve the mortality rate in sepsis is a continuous effort within the medical community.

In June 2017 Chest published a before-after retrospective study investigating the effect of ascorbic acid, steroids, and thiamine administration in patients with sepsis. Their data showed that the mortality rate was 8.5.% in the treatment group and 40.4% in the control group. Post-publication editorial criticized the paper for publishing "spurious findings, biased results, and overstated conclusions," noting that a >30% absolute risk reduction is "biologically implausible."1,2

In October 2019, the CITRIS-ALI RCT was published in JAMA and investigated whether IV vitamin C reduced organ failure scores or  biomarkers of inflammation and vascular injury in patients with sepsis +  acute respiratory distress syndrome (ARDS). Primary outcomes demonstrated no significant drop in SOFA scores or other organ dysfunction markers; however, secondary outcome of reduction in mortality was seen. Critics note that this finding may be misleading, as there is a large confidence interval and the study was not powered to detect this outcome. Additionally, there were a large number of secondary outcomes which makes finding one significant by chance more likely.3,4

In January 2020 the VITAMIN trial was published in JAMA and investigated the difference in resolution of sepsis in patients receiving  ascorbic acid, hydrocortisone, and thiamine vs hydrocortisone alone. Primary outcomes were time alive and time free of vasopressors. Between the experimental and control group there was no significant difference. One secondary outcome, change in SOFA score, was seen to be significantly lower in the experimental group. Overall, study authors determined that there was no faster resolution of septic shock in patients receiving the experimental cocktail.5

More recently in July 2020, the ORANGES trial was published in Chest, which evaluated yet again whether ascorbic acid, hydrocortisone, and thiamine improved clinical outcomes in sepsis and septic shock. In this trial the primary outcome was resolution of shock as measured by discontinuation of vasopressor support as well as change in SOFA score. They found a statistically significant reduction in the time to shock resolution in the experimental group vs control without associated significant change in SOFA score. It is important to note that the primary outcome of this study was originally 28-day mortality, but was changed after full data collection was gathered which makes the overall interpretation of the study more suspect.3

Enter the ACTS trial. This study aimed to further assess the effects of ascorbic acid, corticosteroids, and thiamine on organ injury and function in severe sepsis patients.

Design
Randomized, double-blinded, multicenter clinical trial

Population
Inclusion Criteria:

  • 18 years of age or older
  • Suspected or confirmed infection
  • Receiving vasopressors

Exclusion Criteria:

  • Allergic to study drugs
  • Specific clinical indication for any of the study drugs
  • G6PD deficiency
  • Hemochromatosis
  • Receiving renal replacement therapy
  • Expected survival <24 hours
  • Protected populations

Primary Outcome

  • Change in the SOFA score between enrollment and 72-hour follow-up

Secondary Outcomes

  • Kidney failure
  • All cause mortality after first 30 days
  • Ventilator-free days during first 7 days
  • Shock free days during first 7 days
  • Days free ICU stay during first 28 days

Key Results
4569 patients met inclusion criteria, 831 were eligible, 205 randomized and 200 received at least 1 dose of the study drugs

Primary Outcomes: 9 patients (9.1%) died in the placebo group and 10 patients (9.9%) died in the intervention group. No statistically significant difference between intervention group and control group for the primary outcome of change in SOFA score. (mean difference, −0.8; 95% CI, −1.7 to 0.2; P = .12)

Secondary Outcomes (adverse events):
No significant difference in the rates of:

  • Kidney Failure
  • 30 day mortality
  • Ventilator free days
  • Days free from the ICU

Shock free days was fewer by 1 day in the placebo group (p=0.02)

Strengths
Randomize, double blinded, multicenter

 

Limitations

  • Large number of screened (94%) but non-randomized patients
  • Long time between vasopressor initiation to study drug administration
  • Early discharge from the  ICU prior to full treatment course
  • Primary outcome is not patient-centered
  • 14 hours between randomization and treatment regimen given

EM Take-Aways
Despite previously published data, this trial demonstrated that in patients suffering from septic shock, administration of ascorbic acid, corticosteroids and thiamine do not reduce rates of organ injury compared to placebo. It is important to recognize that the primary outcome is not a patient-centered outcome, but rather a marker of organ function. Even if statistical significance was seen, relating this to patient outcomes is difficult. Patients in this study required vasopressor therapy and were very sick at the start of the study. Further studies may focus on sepsis patients who are not in shock, to see if early intervention reduced progression to shock states.


References

  1. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229-38.
  2. Møller MH, Laake JH, Myburgh JA, Alhazzani W, Perner A. The Magic Bullet in Sepsis or the Inflation of Chance Findings?. Chest. 2017;152(1):222-3.
  3. Fowler AA, Truwit JD, Hite RD, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019;322(13):1261–1270. 
  4. https://rebelem.com/citris-ali-vitamin-c-in-patients-with-sepsis-and-severe-acute-respiratory-failure/
  5. Fujii T, Luethi N, Young PJ, et al. 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. JAMA. 2020;323(5):423–431. 

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