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LOVIT trial – Final Nail in the Coffin for Vit C in Septic Shock?
Dr Swapnil Pawar
Blog Written by Dr Jose Chacko
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.
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.
Common to both groups
Thiamine and glucocorticoid administration were based on clinician judgment. Telephone interview at 6 months.
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.
Similar between two groups
Median stay was 6 days (3 to 12) in the ICU and 16 days (8 to 32) in the hospital.
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)
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
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
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
|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
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
|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
|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
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.