LOVIT

In Review

Lamontagne, F, et al. "Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit". New England Journal of Medicine. 2022. 386:2387-2398.
PubMed • ClinicalTrials.gov

Clinical Question

In adults with sepsis requiring vasopressor support, does the addition of high-dose Vitamin C decrease mortality and persistent organ dysfunction at 28 days, as compared to placebo?

Bottom Line

In adults with sepsis who were receiving vasopressor therapy in the ICU, high dose intravenous vitamin C resulted in a higher risk of mortality or persistent organ dysfunction at 28 days as compared to placebo.

Major Points

Like Helen of Troy, a single centre retrospective, observational trial published in 2017, launched over 40 trials attempting to replicate the profound benefit demonstrated in patients with sepsis. Humans are one of the few mammals who's cells do not produce ascorbic as an acute phase reactant in times of infection. Theoretically supplementing with high doses may improve outcomes. There is a physiological ceiling to oral absorption of ascorbic so intravenous route must be utilized.

The phase 3, multicenter, randomized, controlled trial, Lessening Organ Dysfunction with Vitamin C (LOVIT), was one of these that again, was unable to find benefit and suggests instead harm associated with high dose vitamin C. This trial randomized patients to receive either Vitamin C 50mg/kg intravenously every 6 hours for 16 doses (n=429) or matched placebo (n=434). The were randomized from 35 adult medical/surgical ICUs in Canada, FRance, and New Zealand. For their primary outcome, the authors found worse outcomes in the composite of death or persistent organ dysfunction at 28 days, 44.5% in the vitamin C group vs. 38.5% in the placebo group (RR 1.21; 95% CI 1.04-1.4). In their secondary outcomes there was no difference for median number of days without organ dysfunction in the ICU by day 28, death at 6 months, or functional assessment at 6 months via telephone interview. In their subgroup analysis, they found a higher rate of mortality in females, patients with a Clinical Frailty Scale 1-4, or patients that did not meet the Sepsis-3 definition of septic shock. For adverse effects and safety there were no statistical differences between groups.

There were some limitations to the trial, including no assessment for the appropriateness of antimicrobial therapy, generalizability due to patients coming from middle-high income countries, and the primary outcome being an unbalanced composite. Despite that, this trial demonstrated worse outcomes for those patients exposed to high-dose intravenous Vitamin C (ascorbic acid).

Guidelines

Surviving Sepsis Guidelines 2021, adapted

• Adults with sepsis or septic shock, suggest against intravenous Vitamin C

Design

• Multicenter, Parallel-Group, Blinded, Randomized, Placebo-Controlled Trial
• N=863
  • Vitamin C (n=429)
  • Placebo (n=434)
• Setting: 35 adult medical–surgical ICUs in Canada, France, and New Zealand
• Enrollment: 14 November 2018 to 19 July 2021
• Follow-up: 6 months
• Analysis: Intention-to-treat
• Primary Outcome: Death or persistent organ dysfunction at 28 days

Population

Inclusion Criteria

• Adult (≥18 years of age)
• primary diagnosis of proven / suspected infection
• Receiving any dose of vasopressor via continuous infusion
• Admitted to an ICU less than 24 hours

Exclusion Criteria

• Known Glucose-6-phosphate dehydrogenase deficiency
• Pregnancy
• Known allergy to vitamin C
• Known kidney stones within the past 1 year
• Receipt of open-label intravenous vitamin C during the current hospitalization (unless incorporated in parenteral nutrition)
• Expected death or withdrawal of life-sustaining treatments within 48 hours
• Previously enrolled in this study or study where co-enrollment not allowed

Baseline Characteristics

Vitamin C Group displayed

• Demographics: Mean age 65 years, 35.2% female
• ICU Admission: 81.6% Medical, 16.1% Emergency Surgery, 2.3% Elective surgery
• Physiologic parameters: Median APACHE II score 24.2, medial SOFA score 10.2, Median Clinical Frailty Scale 3.8,
• Primary site of infection: 33.8% Pulmonary, 31% gastrointestinal, 12.8% blood, 12.8% skin and soft tissue, 0.5% Central nervous system, 7% other, 8.6% SARS-CoV-2 positive
• Labs: Median Lactate 3.4, median Vitamin C 20.6 micromol
• Median time from ICU admission to randomization 12.9 hours
• Treatments: 46.4% glucocorticoids, 68.5% mechanical ventilation, 10.7% renal-replacement therapy, 99.8% vasopressor infusion

Interventions

• Vitamin C (ascorbic acid) 50mg/kg IV over 30 to 60 minutes every 6 hours for 96 hours (16 doses total)
• Thiamine and glucocorticoids were open-label at the discretion of the treating clinician

Outcomes

Comparisons are Vitamin C vs. Placebo.

Primary Outcomes

Death or persistent organ dysfunction at 28 days

44.5% vs. 38.5% (RR 1.21; 95% CI 1.04-1.4)

Secondary Outcomes

Median number of days without organ dysfunction in the ICU by day 28

17 vs. 19.1 (difference -2.43; 95% CI -7.23 to 2.37)

Death at 6 months

45.8% vs. 43.4% (HR 1.14; 95% CI 0.93 to 1.39)

EQ-5D-5L at 6 months on visual analogue scale

65.8 vs. 63.8 (difference 2.04; 95% CI -1.97 to 6.05)

Subgroup Analysis

Female, mortality

47.7% vs. 35.8% (RR 1.39; 95% CI 1.10 - 1.76)

Clinical Frailty Scale 1-4, mortality

42.6% vs. 37% (RR1.22; 95% CI 1.02 - 1.46)

Not meeting Sepsis-3 definition of septic shock

40.9 % vs. 28.6% (RR 1.41; 95% CI 1.03 - 1.94)

Adverse Events

Stage 3 kidney disease

37.8% vs. 37.9% (RR 1.00; 95% CI 0.85 to 1.19)

Hypoglycemia

6.1 % vs. 5.1% (RR 1.25; 95% 0.73 to 2.14)

Serious Adverse events

0.2% vs. 0

Criticisms

• Antimicrobial appropriateness was not assessed
• Generalizability may be impacted as patients randomized from middle-high income countries
• primary outcome was a composite

Funding

• Lotte and John Hecht Memorial Foundation
• Nova Biomedical Canada provided glucometers, testing strips, and control solutions (StatStrip Express) to sites who requested