Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients

Abstract

Background: Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study.

Methods: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D₃ supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D₃ or matched placebo. The primary end point was 90-day all-cause, all-location mortality.

Results: A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean 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% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P = 0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality.

Conclusions: Early administration of high-dose enteral vitamin D₃ did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.).

Figure 1 (facing page).. Screening, Enrollment, and Follow-up.

Patients may have had more than one reason for being excluded after the assessment of eligibility, and patients who underwent randomization may have had more than one reason for not receiving the assigned intervention. ICU denotes intensive care unit, and LC-MS-MS liquid chromatography-tandem mass spectrometry.

Figure 2.. Survival to Day 90 in the Primary Analysis Population.

This figure is descriptive and not intended for inference of effects.

Figure 3.. Mortality to Day 90 According to Baseline 25-Hydroxyvitamin D Level among All Patients Who Underwent Randomization.

I bars represent 95% confidence intervals. Plasma 25-hydroxyvitamin D concentrations were measured by liquid chromatography-tandem mass spectrometry. Estimates were obtained from the quadratic smoothing spline in each treatment group with prespecified knots at plasma 25-hydroxyvitamin D levels of 5, 10, 15, 20, 25, and 30 ng per milliliter and pointwise 95% bootstrap confidence intervals. To convert the values for 25-hydroxyvitamin D to nanomoles per liter, multiply by 2.496.