Vitamin D3, Placebo Similar for Critically Ill, Vitamin D-Deficient Patients

Adit Ginde, MD

Early administration of high-dose vitamin D₃ did not perform better than placebo in terms of 90-day mortality or nonfatal outcomes for critically ill, vitamin D-deficient patients, findings of a recent study showed.

Adit Ginde, MD, vice chair of research at the Department of Emergency Medicine at the University of Colorado School of Medicine, and his team of investigators conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D₃ use in vitamin D-deficient patients who were at high risk for death. The primary endpoint of the analysis was 90-day all-cause, all-location mortality.

The 90-day mortality was 23.5% in the vitamin D group and 20.6% in the placebo group (difference, 2.9 percentage points; 95% CI, -2.1—7.9; P = .26).

The findings of the study do not support early testing or treatment of vitamin D deficiency in critically ill patients.

Patients were enrolled in the study within 12 hours of the clinician’s decision to admit the patient to the intensive care unit (ICU). Enrolled patients were adults with 1 or more acute risk factors for death or lung injury that directly contributed to the need for the admission to the ICU.

The patients were randomly assigned to either receive a single enteral dose of 540,000 international units of vitamin D₃ or liquid form, matched placebo administered within 2 hours after randomization. In total, 690 patients were in the vitamin D group and 668 patients were in the placebo group.

The investigators’ primary analysis included 1078 patients who had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing—not just screening during point-of-care. The day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% CI, 31.5—39.6).

In the screened-deficient group—those who were tested at the point-of-care&mdash;90-day all-cause mortality was 23.3% in the vitamin D group and 20.9% in the placebo group (difference, 2.5 percentage points; 95% CI, -2—6.9; P = .28).

Observed mortality was higher in the vitamin D group than the placebo group for patients in the primary analysis group with sepsis or infection. In the screened-deficient population, mortality was higher for patients with pre-hospital facility residence, pneumonia, infection, and prerandomization acute respiratory distress syndrome.

Mortality to day 28, hospital mortality to day 90, facility length of stay, and ventilator-free days did not differ significantly between the groups.

The findings of a previous phase 2 trial showed that vitamin D supplementation given to vitamin D-deficient, critically ill patients was linked to lower mortality than placebo at 28 days (21.9% vs 28.6%, P = .14) and at 6 months (35% vs 42.9%, P = .009).

Similar to the phase 2 trial, the phase 3 trial included the vitamin D₃ regimen (a single enteral dose of 540,000 international units), the threshold for vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]), and a focus on critically ill patients.

In the phase 3 trial, however, the investigators focused on patients with specific higher-risk conditions and early intervention before ICU admission.

Current studies are evaluating the effect of vitamin D supplementation in patients with severe vitamin D deficiency, other subgroups that could benefit, and long-term outcomes.

The study, “Early High-Dose Vitamin D₃ for Critically Ill, Vitamin D-Deficient Patients,” was published online in the New England Journal of Medicine.