Let’s Get Our ACTS Together: The Metabolic Cocktail and Septic Shock Again

Background: Though it’s been stated numerous times on this blog, it bears repeating: the pillars of sepsis care remain early identification of sepsis, early appropriate empiric antibiotics, source control, and supportive care. The focus should be on getting the basics right but, it is important to evaluate whether other adjunctive therapies can help decrease mortality in a common and frequently fatal condition. Ascorbic acid and thiamine deficiency have been described in patients with sepsis and are thought to be due to reduced intake and increased metabolic demands.  Corticosteroids have had mixed results but seem to improve shock reversal in patients with septic shock based on best available evidence (Link is HERE). There have been a slew of RCTs evaluating this metabolic cocktail (vitamin C, thiamine, & corticosteroids) in recent months. Though biologically plausible, this treatment approach has not been shown to improve patient-oriented outcomes.

Paper: Moskowitz A et al. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized clinical Trial. JAMA 2020. PMID: 32809003

Clinical Question: Does the combination of ascorbic acid, corticosteroids, and thiamine attenuate organ injury in patients with septic shock?

What They Did:

• Multicenter, randomized, blinded, placebo-controlled superiority clinical trial
• 14 centers in the United States
• Patients randomized to:
  • IV ascorbic acid 1500mg, hydrocortisone 50mg, and thiamine 100mg every 6 hours for 4 days
  • Matching placebo in matching volumes

Outcomes:

• Primary: Change in Sequential Organ Failure Assessment (SOFA) Score between enrollment and 72 hours
• Secondary:
  • Kidney failure (Development of grade ≥3 kidney disease)
  • 30d Mortality
  • Ventilator-free days during the first 7 days
  • Shock-free days during the first 7 days
  • Days free of ICU during first 28 days
  • All-cause mortality to ICU discharge
  • All-cause mortality to hospital discharge
  • Posthospitalization disposition in survivors to hospital discharge
  • 72-hour change in individual SOFA score components
  • Delirium on day 3

Inclusion:

• Age ≥18 years
• Suspected or confirmed infection
• Receiving vasopressors due to sepsis

Exclusion:

• Allergic to study drug components
• Clinical indication for any of the study drugs
• Symptomatic kidney stones within the last year
• Glucose-6-phosphate dehydrogenase deficiency
• Hemochromatosis
• Receiving kidney replacement therapy (changed from stage 3b chronic kidney disease after 19^th enrolled patient)
• Not expected to survive 24 hours
• Member of a protected population (i.e. pregnant, prisoner)

Results:

• 205 patients enrolled
  • >800 patients were determined to be eligible but only a small portion were actually randomized
  • 98% of patients received at least 1 dose of study drug, completed the trial and included in the analysis
  • Both groups received a median of 2000cc of fluids prior to study drug
  • Median time from vasopressor to initiation of first study drug was ≈14hrs
  • ≈45% of patients were on mechanical ventilation
  • ≈20% had ARDS
  • Median lactate level 16.2mg/dL
• Change in SOFA Score From Baseline to 72hrs (Primary Outcome):
  • Metabolic Cocktail: 9.1 to 4.4 (-4.7)
  • Placebo: 9.2 to 5.1 (-4.1)
  • Adjusted mean difference -0.8; 95% CI -1.7 to 0.2; p = 0.12

• Incidence of Kidney Failure
  • Metabolic Cocktail: 31.7%
  • Placebo: 27.3%
  • Adjusted risk difference 0.03; 95% CI 0.8 to 2.2; p = 0.26
• 30d Mortality:
  • Metabolic Cocktail: 34.7%
  • Placebo: 29.3%
  • HR 1.3; 95% CI 0.8 to 2.2; p = 0.26
• Median Shock Free Days:
  • Metabolic Cocktail: 5 (Range 3 to 5)
  • Placebo: 4 (Range 1 to 5)
  • Median difference 1.0 days; 95% CI 0.2 to 1.8 days; p < 0.1
• No difference in ventilator-free days
• No unexpected serious adverse events related to study drug
• Most common serious adverse events:
  • Hyperglycemia
    • Metabolic Cocktail: 12 patients
    • Placebo: 7 patients
  • Hypernatremia:
    • Metabolic Cocktail: 11 patients
    • Placebo: 7 patients

Strengths:

• Multicenter, randomized, blinded, placebo-controlled superiority clinical trial (all the words we like to see when evaluating a trial)
• Site investigators, research staff, clinical staff, and patients blinded to group assignment for the duration of the study
• Study drug and placebo were delivered in light-protected bags in the same way to maintain blinding
• Baseline characteristics of patients were well matched between groups
• Based their 2 point SOFA score decrease from previous literature showing that a 2 point decrease or more increase in SOFA score from baseline is associated with an approximate 10% increase in mortality

Limitations:

• Despite enrolling patients from 14 centers in the United States, from February 2018 to November 2019, were only able to recruit 205 patients.
  • 4569 patients assessed for eligibility of which 831 were eligible but not randomized
• Non-patient centered primary outcome
• This means this was a convenience sample and not a consecutive sample of patients which could cause selection bias
• Ongoing or planned corticosteroid use was the most common exclusion criterion which removes patients more likely to benefit from this component of the metabolic cocktail
• Some patients were discharged alive from the ICU within 96hrs of enrollment, meaning that they did not receive a full 4-day course of study drug
• Study was not powered for subgroup analyses or small differences in mortaliy

Discussion:

• Summarizing the results of previous trials:
  • Marik before and after trial: Huge benefit
  • VITAMINS: Highest quality trial to date, showed no benefit
  • CITRIS-ALI: Showed a reduction in 28-day mortality (i.e. 17%).
    • This was a secondary outcome in a trial with 46 secondary outcomes. The mortality benefit seen could have been from chance alone.
    • Patients had to have septic shock and ARDS to be enrolled, which is not the case in the current trial
    • Additionally, CITRIS-ALI used a higher dose of ascorbic acid 50mg/kg compared to the current trial
  • HYVCTTSSS: Showed a reduction in 28-day mortality (i.e. 7.5%)
    • Study underpowered (Was trying to detect a 30% 28day mortality difference)
  • ORANGES: Decrease in vasopressor duration
• Time from vasopressor initiation to study drug administration was 13.5hrs, but a shorter time to study drug administration may have resulted in improved outcomes. However, earlier drug administration may also be irrelevant. We don’t know the time from vasopressor to metabolic cocktail in the Marik study.  Additionally, we don’t know the time of onset of sepsis, so time, may mean nothing
• In the supplementary index, it shows there was a degradation in the number of doses of medication used by day, but no explanation as to why this occurred

Author Conclusion: “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”

Clinical Take Home Point: Use of the metabolic cocktail in septic shock did not result in a reduction in SOFA scores during the first 72 hours after enrollment or other patient oriented outcomes.  This is yet another study showing no benefit in the routine use of the metabolic cocktail in septic shock.

References:

1. Moskowitz A et al. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized clinical Trial. JAMA 2020. PMID: 32809003

For More Thoughts on This Topic Checkout:

• REBEL EM: The Marik Protocol – Have We Found a “Cure” for Severe Sepsis and Septic Shock?
• REBEL EM: CITRIS-ALI – Vitamin C in Patients with Sepsis and Severe Acute Respiratory Failure
• REBEL Cast: REBEL Cast Ep74 – Is it all About the VITAMINS in Sepsis?
• REBEL EM: The HYVCTTSSS Trial – The “Metabolic Cocktail” in Another RCT
• REBEL EM: The ORANGES Trial – Why You Can’t Just Read the Abstract
• St. Emlyn’s: Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock. The ACTS Randomized Clinical Trial

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