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LOVIT trial – Final Nail in the Coffin for Vit C in Septic Shock?

Dr Swapnil Pawar June 25, 2022 4344


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    LOVIT trial – Final Nail in the Coffin for Vit C in Septic Shock?
    Dr Swapnil Pawar

Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit

Blog Written by Dr Jose Chacko

Setting

 

Thirty-five medical–surgical ICUs in Canada, France, and New Zealand.

 

Included: Adult patients with infection, receiving vasopressors, who were admitted to the ICU for no longer than 24 hours

 

Excluded: Patients with contraindications for vitamin C, those who received open-label vitamin C, expected to die, or undergo withdrawal of life-support measures within 48 hours.

 

Intervention

 

Vitamin C, 50 mg/kg in 50 ml of 5% dextrose or normal saline, administered 6-hourly, over a period of 30–60 minutes. Treatment continued for 96 hours for a maximum of 16 doses, provided the patients remained in the ICU.

 

Control

Matching placebo

Common to both groups

Thiamine and glucocorticoid administration were based on clinician judgment. Telephone interview at 6 months.

 

Statistical analysis

Sample size calculated based on 50% risk of death or organ dysfunction in the control group.

Each group included 385 patients for 80% for a difference of 10 percentage points in the primary outcome with a two-sided type I error rate (alpha) of 0.05. The sample size was later increased to include the original sample size without COVID-19.

 

Baseline characteristics

Similar between two groups

Median stay was 6 days (3 to 12) in the ICU and 16 days (8 to 32) in the hospital.

 

Outcomes

Primary outcome

Composite primary outcome: death or persistent organ dysfunction (vasopressor use, invasive mechanical ventilation, or renal-replacement therapy) at 28 days

 

191 of 429 patients (44.5%) vs. 167 of 434 patients (38.5%) (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01)

 

No difference after applying best- or worst-case scenario for one patient with unknown status of primary outcome

 

On adjusted analysis after adjusting for baseline characteristics, the risk ratio for the primary comparison was 1.15 (95% CI, 0.90 to 1.47)

 

Secondary outcomes

 

28-day mortality: 152 patients (35.4%) vs. 137 (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40).

 

Median number of days without organ dysfunction at day 28:  17 vs. 19.5 (median difference, −2.43 days; 95% CI, −7.23 to 2.37)

 

No difference between groups in SOFA scores, biomarkers, 6-month survival, and health-related quality of life.

 

No difference between groups in prespecified safety outcomes. Four adverse events in the vitamin C group and 1 in the placebo group. In the vitamin C group, 1 patient had a serious adverse event of anaphylaxis and another had a severe hypoglycemic episode

 

Limitations

 

  1. Nine patients who had undergone randomization did not contribute data to the primary analysis; of these patients, eight had not received either vitamin C or placebo and had met the prespecified criteria for exclusion after randomization.

2. Only one patient who withdrew consent could not be included in the intention-to-treat analysis.

3. Applicability to low- and middle-income countries

 

Comparison of all trials published on this topic –

Study (year) Type Population Intervention Control Outcomes (intervention vs. control)
Marik et al. Electronic health record -based retrospective before-after study Primary diagnosis of severe sepsis or septic shock and a procalcitonin level 2 ng/mL 47 patients

Vitamin C 1.5 g/6h every 6 h x 4 days

Hydrocortisone 50 mg/6h x 7 days thiamine 200 mg/12 h x 4 days

 

47 patients

Hydrocortisone 50 mg/6h at clinician discretion

Hospital mortality: 8.5% vs. 40.4% (P < .001)

Mean vasopressor duration:  54.9 vs. 28.4 h (P < .001)

CITRIS-ALI Randomized controlled trial Sepsis, ARDS 84 patients

Vitamin C 50 mg/kg/6h x 4 days

83 patients

Placebo

Change in mean modified SOFA score from baseline to 96 hours: 3 vs. 3.5 points; difference −0.10; 95% CI, −1.23 to 1.03; P = .86

C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, −8.2 to 24.11; P = 0.33); thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, −2.8 to 4.2; P = .70)

VITAMINS Randomized controlled trial Septic shock 107 patients

Vitamin C 1.5 g/6 h Hydrocortisone 50 mg/6h Thiamine 200 mg/12 hours

104 patients

Hydrocortisone 50 mg/6h

Time alive and off vasopressor until day 7: 122.1 (76.3-145.4 hours) vs. 124.6 hours (82.1-147.0 hours) P = 0.83);

90-day mortality: 28.6% vs. 24.5% (hazard ratio, 1.18; 95% CI, 0.69-2.00)

 

VICTAS Randomized controlled trial Sepsis-induced respiratory or cardiovascular dysfunction 252 patients

Vitamin C 1.5 g/6h, thiamine 100 mg/6h, and hydrocortisone 50 mg /6 hours

 

249 patients

 

Placebo

Median ventilator- and vasopressor-free days: 25 (IQR, 0-29 days) vs. 26 days (IQR, 0-28 days). Median difference: −1 day (95% CI, −4 to 2 days; P = .85)

30-d mortality: 22% vs. 24%

LOVIT Randomized controlled trial Proven or suspected infection, on vasopressors, not longer than 24 hours in ICU 429 patients

Vitamin C 50 mg/kg/6h x 96 hours

434 patients

Placebo

Death or persistent organ dysfunction on day 28: 44.5% vs. 38.5% (risk ratio, 1.21; 95% CI, 1.04 to 1.40; P=0.01)

28-d mortality: 35.4% vs. 31.6% (risk ratio, 1.17; 95% CI, 0.98 to 1.40)

Persistent organ dysfunction on day 28: 9.1% vs. 6.9% risk ratio, 1.30; 95% CI, 0.83 to 2.05

ATESS Randomized controlled trial Septic shock 53 patients

Vitamin C 50 mg/kg (max single dose: 3g), thiamine 200 mg every 12 h x 48 h

58 patients Difference in ΔSOFA (baseline- 72 h) scores 3, (− 1 to 5) vs. 3, (0–4), p = 0.96

No difference in mortality at 7, 28, and 90 days. No difference in ICU or hospital mortality. No difference in shock reversal, vasopressor-free days

Summary – 

This trial has given us a clear answer and we strongly believe that there is no role for intravenous b=vitamin C in patients with septic shock.

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