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

The New England journal of medicine

Dec 2019

DOI: 10.1056/NEJMoa1911124

Citations:191

Influential Citations:12

Interventional (Human) Studies

Enhanced Details

Methods

Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial in adults with critical illness and vitamin D deficiency (25-hydroxyvitamin D <20 ng/mL). Randomization within 12 hours of ICU admission decision; primary analysis included 1,078 deficiency-confirmed patients; conducted in 44 U.S. hospitals; participants had acute risk factors for death (e.g., pneumonia, sepsis, shock, mechanical ventilation).

Intervention

Cholecalciferol (Vitamin D3), 540,000 IU, single enteral dose (oral or via nasogastric/orogastric tube), administered within 2 hours after randomization; no additional vitamin D supplementation beyond the loading dose.

Results

Early high-dose enteral vitamin D3 did not improve 90-day mortality or other major outcomes in vitamin D–deficient critically ill adults. 90-day mortality: 23.5% in the vitamin D group (125/531) vs 20.6% in the placebo group (109/528); difference 2.9 percentage points (95% CI, −2.1 to 7.9; P=0.26). No significant differences in secondary endpoints or safety, and no interaction with baseline 25-hydroxyvitamin D levels. Conclusion: early vitamin D supplementation provides no advantage over placebo in this setting and does not support routine testing or treatment of vitamin D deficiency in critically ill patients.

Limitations

Exclusion of patients later in the course of critical illness may bias toward less severe illness and limit generalizability; outcomes not assessed in those not randomized after screening; early stopping for futility reduces power to detect small benefits; only a single loading dose with no subsequent supplementation; reliance on complete-case analyses may bias if data are not missing completely at random; 90-day follow-up limits assessment of longer-term outcomes.

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.). show less