The ATESS Trial: Time to Let Go of the Metabolic Cocktail

Background: The only well-established treatments for sepsis and septic shock are antibiotic therapy and source control.  Septic shock, the most severe form of sepsis, is characterized by circulatory and cellular metabolism abnormalities.  There have been a host of randomized controlled trials evaluating the use of vitamin C, thiamine, and corticosteroids (i.e. metabolic cocktail) to help mitigate dysregulated host responses in the hopes of improving patient-oriented outcomes. Thus far none of the randomized trials have shown improvements in mortality and shown mixed results with shock reversal (see tables below).

DISCLAIMER: Both of the tables below are oversimplified as these trials are not of equal methodology.  The highest quality studies are VITAMINS, CITRIS-ALI and ACTS.

*VITAMINS Trial compared Vitamin C, Thiamine, & Hydrocortisone to Hydrocortisone

Paper: Hwang SY et al. Combination Therapy of Vitamin C and Thiamine for Septic Shock: A Multicentre, Double-Blinded Randomized, Controlled Study. Intensive Care Med 2020. PMID: 32780166

Clinical Question: Does “early” combination therapy with vitamin C and thiamine improve recovery from organ failure in patients with septic shock compared to placebo?

What They Did:

• Ascorbic Acid and Thiamine Effect in Septic Shock (ATESS) Trial
• Multicenter, double-blind, randomized, controlled trial conducted in 4 EDs in South Korea
• Patients randomized 1:1 to:
  • Treatment group: IV Vitamin C 50mg/kg, max single dose 3g + Thiamine 200mg q12hrs for 48hrs
  • Placebo group: Identical volume 0.9% saline with same protocol

Outcomes:

• Primary: Change in SOFA score from baseline to 72hrs
• Secondary: 18 secondary outcomes were predefined
  • 7d, 28d, 90d, in-hospital, and ICU mortality
  • Shock Reversal (Defined as maintaining a MAP of 60mmHg or more for longer than 24hrs after discontinuation of all vasopressors)

 Inclusion:

• Adult patients (19 to 89 years)
• Presenting to an ED
• Diagnosed with septic shock during ED stay (Septic shock defined as: Sepsis with persisting hypotension requiring vasopressors to maintain a MAP ≥65mmHg + a serum lactate >2mmol/L despite adequate fluid challenge)

Exclusion:

• Transferred from another hospital with vasopressor administration or mechanical ventilator support
• Patients who had limitations on treatment (i.e. DNR)
• Patients with underlying terminal-stage disease
• Taking 1g/day of vitamin C or receiving IV thiamine prior to enrollment
• Cardiac arrest prior to enrollment
• Diagnosed with renal or ureteral stones
• Meeting inclusion criteria for >24hours after ED arrival
• Declined to participate in trial

Results:

• 111 patients enrolled
• Median SOFA score at enrollment = 8
• Median time to study drug administration after ED arrival
  • Treatment group = 8.4hrs (Range 5.7 to 14.9hr)
  • Placebo group = 9.9hrs (Range 7.4 to 15.6hrs)
• Change in SOFA Score From Baseline to 72hrs (Primary Outcome):
  • Treatment Group: 3 (Range -1 to 5)
  • Placebo Group: 3 (Range 0 to 4)
  • P = 0.96
  • Subgroup analysis showed no difference in change in SOFA score at 72hrs between groups when looking at multiple factors including adjunctive steroids, infection focus (respiratory vs non-respiratory), vasopressor requirement, deficiencies in vitamin C or thiamine
• 28d Mortality:
  • Treatment Group: 20.8%
  • Placebo Group: 15.5%
  • P = 0.47
  • Also, no difference at 7d or 90d between groups
• Shock Reversal:
  • Treatment Group: 83%
  • Placebo Group: 84.5%
  • P = 0.83
• No other secondary outcomes showed significant differences between groups including:
  • Ventilator-free days
  • New onset or worsening AKI
  • Reduction of CRP for 72hrs
  • Reduction of procalcitonin
• No adverse events reported in the treatment group

Strengths:

• Randomized, double-blind clinical trial
• Patients, clinicians, and researchers were blinded to allocated groups throughout the trial
• Co-interventions were performed based on the latest Surviving Sepsis Campaign guidelines
• Used an intention-to-treat analysis which generalizes with clinical practice outside of a clinical trial
• Baseline characteristics of the two groups were similar including age, sex, comorbidities, source of infection, laboratory tests, and severity indexes

Limitations:

• Primary outcome of change in SOFA score at 72hours is a surrogate outcome of organ failure and not patient centered
• If baseline SOFA score was unknown it was assumed to be 0, which would bias the results
• Selection bias: 554 patients assessed for eligibility and 438 excluded from the analysis. 192 of these were patients who declined to participate.  This is more than double the number of patients enrolled in the trial
• Small number of patients enrolled. Power calculation was looking specifically at improvements in organ function, but larger sample size would be required to estimate effects on mortality
• Intra-abdominal infection accounted for almost half of the cases of septic shock with over 50% of patients having solid or hematologic malignancy which may not generalize to typically septic shock patients seen
• Study drugs included were only vitamin C and thiamine and not steroids

Discussion:

• This is now the 6^th RCT on the metabolic cocktail in septic shock since the original Marik before and after trial. None of which have shown a mortality benefit.
• The primary outcome of this trial was exactly the same as the ACTS trial (change in SOFA score at 72hrs). Both trials showed no difference in this outcome
• In this trial the addition of vitamin C and thiamine showed no differences in mortality, shock reversal, vasopressor-free days, ventilator free days or ICU free days.
• Some key differences between this trial and previous RCTs on this topic:
  • Over 50% of patients received glucocorticoids in this trial instead of all patients. There was no difference in 72hr change in SOFA score between groups regardless of glucocorticoid administration
  • Interval between doses of vitamin C & thiamine administration was longer (12hr vs 6hr) but duration of treatment was shorter (48hr vs 96hr or more) compared to previous trials
  • Vitamin C and thiamine levels were all normalized in all patients at 72hrs in the treatment group but not the placebo group, however shock reversal occurred within 72hrs in most cases in both groups
  • The time from meeting eligibility criteria to first study drug administration was relatively short compared to previous trials. Patients underwent initial resuscitation with fluids and antibiotics before meeting shock eligibility criteria. Earlier administration of vitamins in addition to other bundle-based interventions for sepsis and septic shock, should have resulted in more benefit to patients in the treatment group if there was going to be a benefit
• The time from meeting eligibility criteria to study drug administration was 3.1hrs in the treatment group and 3.8hrs in the placebo group. Additionally, the time from randomization to the first study drug was 0.8hrs in the treatment group and 1.2hrs in the placebo group
• There was no difference in adjunctive steroid administration, time from ED arrival to first antibiotic and vasopressor administration, intravenous fluids, and use of mechanical ventilation between groups

• No difference between groups at enrollment on median vitamin C levels or vitamin C deficiency, but vitamin C level was significantly higher in the treatment group than in the placebo group at 72hrs. There were no cases of vitamin C deficiency in the treatment group at 72hrs while vitamin C deficiency persisted in 55.4% of the placebo group.  There was no significant differences in thiamine deficiency between the two groups at enrollment or at 72hours between groups
  • ½ of patients had vitamin C deficiency and 1/10^th of patients had thiamine deficiency at the time of study enrollment

• The CITRIS-ALI trial, comparing high dose vitamin C therapy with placebo hd no effect on 96hr change in SOFA score, but showed a decrease in 96hr and 28 mortality in the treatment group. Patients who died before 96hrs were not included in the primary analysis and therefore death during the assessment period resulted in missing data for patients with high SOFA scores.  This could lead to something called survivorship bias which might paradoxically favor the placebo group with higher mortality. In this trial the number of patients who died within 72hrs was rare and therefore no survivorship bias would be seen

Author Conclusion: “In this study, vitamin C and thiamine administration in early phase of septic shock did not improve organ function compared with placebo, despite improvements in vitamin C and thiamine levels.”

Clinical Take Home Point: This is now the 6^th RCT showing no benefit in the primary outcome (Change in SOFA score at 72hrs in this case).  Although, corticosteroids were not a routine component of the metabolic cocktail, which is different than prior studies, we see no improvement in any of the outcomes including change in SOFA score at 72 hours, 28d mortality, or reversal of shock. Routine use of vitamin C and thiamine supplementation in septic shock should not be recommended at this time. 

References:

1. Hwang SY et al. Combination Therapy of Vitamin C and Thiamine for Septic Shock: A Multicentre, Double-Blinded Randomized, Controlled Study. Intensive Care Med 2020. PMID: 32780166

For More Thoughts on This Topic Checkout:

• The Bottom Line: ATESS

Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)