VITAMINS

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Fujii T, 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.
PubMedFull textClinicalTrials.gov

Clinical Question

Among patients with septic shock, does intravenous administration of vitamin C, thiamine, and hydrocortisone lead to faster resolution of septic shock than hydrocortisone alone?

Bottom Line

Among ICU patients with septic shock, administration of intravenous vitamin C, thiamine, and hydrocortisone do not lead to faster resolution of septic shock when compared to hydrocortisone alone.

Major Points

There are limited therapeutic options in the management of septic shock, and identifying methods to reduce mortality from this condition is imperative.[1] Several small or low-quality studies (ie, non-RCTs) assessed the potential role of vitamin B1 (thiamine) and C in populations with sepsis. One study found a possible reduction in SOFA scores and inflammatory biomarkers with vitamin C administration.[2] One reported lower thiamine levels among patients with sepsis.[3] One reported lower mortality and improved lactate clearance among a cohort treated with thiamine relative to controls not treated with thiamine.[4] The most famous was a 2017 study (on this site known as Hydrocortisone, Vitamin C, and Thiamine in Severe Sepsis and Septic Shock) that reported lower hospital mortality and reduced amount of time requiring vasopressors among a cohort treated with vitamin C, thiamine, and hydrocortisone relative to historical comparisons. An RCT was needed to identify an actual role for these agents.

Published in 2020, the The VitamIn C, HydrocorTisone and ThiAMINe in Patients With Septic Shock (VITAMINS) Trial randomized 216 ICU patients with septic shock to triple therapy with hydrocortisone, vitamin C, and thiamine or thiamine alone in an open-label fashion. The trial met its enrollment target and was likely adequately powered. There was no difference between groups in the primary outcome of duration of time alive free of vasopressor administration. There were no differences in 90 day mortality between groups.

This trial was limited by its open label design and limited capture of key details related to ICU care, like duration of antibiotics and adverse events. This study provides initial evidence that use of thiamine and vitamin C in addition to hydrocortisone is of limited use among ICU patients with septic shock.

Guidelines

As of September 2020, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, open-label, parallel-group, randomized, controlled trial
  • N=216
    • Hydrocortisone, vitamin C, thiamine (n=107)
    • Hydrocortisone alone (n=104)
  • Setting: 10 ICUs in Australia, New Zealand, and Brazil
  • Enrollment: 2018-2019
  • Mean follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcomes: Duration of time alive, free of vasopressor administration

Population

Inclusion Criteria

  • ICU patients
  • Septic shock as primary diagnosis
  • Sepsis-3 guidelines fulfilled within 24 hours of enrollment (i.e., SOFA score increase ≥2, lactate >2 mmol/l, vasopressor dependent for 2 hours)

Exclusion Criteria

  • Age <18 years
  • DNR or imminent death
  • Diagnosis of septic shock >24 hours prior to enrollment
  • Known or strong contraindication to any of the study drugs
  • Indication for study drugs other than septic shock

Baseline Characteristics

From intervention group.

  • Demographics: Age 62 years, 64% male
  • Weight: 82l bs
  • ICU admission source: ED 46%, OR emergent surgery 9%, OR elective surgery 4%, hospital ward 16%, OSH transfer 12%, another ICU 4%
  • PMH: T2DM 21%, CKD 5%
  • Hydrocortisone for sepsis prior to randomization: 42%
  • Baseline therapies: Mechanical ventilation 62%, NE treatment 93%, vasopressin 21%, epi 12%, metaraminol 8%, milrinone 6% RRT 11%
  • Labs: WBC 17.5, plt 162, lactate 4.2, creatinine 1.7
  • AKI: 69%; stage 3 13%
  • Illness severity: APACHE III 77, SOFA 8.6
  • Site of infection: Pulmonary 29%, GI 29%, urinary 17%, skin/soft tissue 13%, bloodstream 8%, other 4%
    • Nosocomial infection: 17%
  • Time from admission in ICU to randomization: 14 hours

Interventions

  • Randomized to a group in an open-label fashion:
    • Hydrocortisone, thiamine, vitamin C (intervention)
    • Hydrocortisone only (control)
  • Treatment used intravenous hydrocortisone (50 mg q6h) or IV vitamin C (1.5 g q6h), IV thiamine (200 mg q12h), and IV hydrocortisone (50 mg q6h) until resolution of shock or for 10 days, whichever came first.
  • Follow up at 28 days post-randomization and 90 days post-randomization.

Outcomes

Comparisons are intervention (three agent therapy) vs. control (hydrocortisone).

Primary Outcomes

Time Alive and free of vasopressors
122.1 vs. 124.6 hours (Difference -0.6; 95% CI -8.3 to 7.2; P=0.83)

Secondary Outcomes

Mortality
At 28 days: 22.6% vs. 20.4% (Difference 2.3; 95% CI -8.9 to 13.4; P=0.69)
At 90 days: 28.6% vs. 24.5% (Difference 4.1; 95% CI -8.0 to 16.1; P=0.51)
Comparison for above using Cox PH model: HR 1.18; 95% CI 0.69 to 2.01; P=0.54
In the ICU: 19.6% vs. 18.3% (Difference 1.4; 95% CI -9.2 to 11.9; P=0.80)
In the hospital: 23.4% vs. 20.4% (Difference 3.0; 95% CI -8.2 to 14.1; P=0.60)
28-d Cumulative vasopressor free days
25.6 vs. 25.8 (Difference -0.2; 95% CI -1.7 to 1.2; P=0.66)
28-d Cumulative mechanical ventilation free days
25.3 vs. 24.8 (Difference 0.4; 95% CI -2.6 to 3.4; P=0.73)
28-d Renal replacement therapy-free days
28.0 vs. 28.0 (Difference 0.0; 95% CI -0.6 to 0.6; P=0.71)
Change in SOFA score at day 3
-2 vs. -1 (Difference -1.0; 95% CI -1.9 to -0.1; P=0.02)
28-d ICU-free days
21.9 vs. 22.1 (Difference -0.2; 95% CI -4.1 to 3.7; P=0.66)
Hospital length of stay (days)
12.3 vs. 12.3 (Difference 0.0; -4.9 to 4.9; P=0.75)

Additional Analyses

AKI
Stage 1: 16.8% vs. 13.5% (Difference 3.4; 95% CI -6.3 to 13.0)
Stage 2: 16.8% vs. 21.2% (Difference -4.3 95% CI -14.9 to 6.2)
Stage 3: 36.4% vs. 37.5% (Difference -1.1 95% CI -14.1 to 12.0)

Adverse Events

Two patients with two separate events were noted to have fluid overload and hyperglycemia, respectively. One patient in the control group had gastrointestinal bleeding.

Criticisms

  • Open label design
  • Unclear utility of the vitamins outside of hydrocortisone use
  • Unclear levels of thiamine.
  • Target mean arterial pressures (MAP) were not collected uniformly.
  • Unclear duration of antibiotics
  • Unclear adverse events.

Funding

  • Alfred Research Trusts Small Project Grant, the Intensive Care Foundation, and the Institutional Development Support Program of the Unified Health System.
  • Multiple authors with disclosures.

Further Reading

  1. Singer M et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016. 315:801-10.
  2. Fowler AA et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med 2014. 12:32.
  3. Donnino MW et al. Thiamine deficiency in critically ill patients with sepsis. J Crit Care 2010. 25:576-81.
  4. Woolum JA et al. Effect of Thiamine Administration on Lactate Clearance and Mortality in Patients With Septic Shock. Crit. Care Med. 2018. 46:1747-1752.