High-Dose Vitamin D3 Administration Is Associated With Increases in Hemoglobin Concentrations in Mechanically Ventilated Critically Ill Adults: A Pilot Double-Blind, Randomized, Placebo-Controlled Trial

Abstract

Background: Anemia and vitamin D deficiency are highly prevalent in critical illness, and vitamin D status has been associated with hemoglobin concentrations in epidemiologic studies. We examined the effect of high-dose vitamin D therapy on hemoglobin and hepcidin concentrations in critically ill adults.

Materials and methods: Mechanically ventilated critically ill adults (N = 30) enrolled in a pilot double-blind, randomized, placebo-controlled trial of high-dose vitamin D₃ (D₃ ) were included in this analysis. Participants were randomized to receive placebo, 50,000 IU D₃ , or 100,000 IU D₃ daily for 5 days (totaling 250,000 IU D₃ and 500,000 IU D₃ , respectively). Blood was drawn weekly throughout hospitalization for up to 4 weeks. Linear mixed-effects models were used to assess change in hemoglobin and hepcidin concentrations by treatment group over time.

Results: At enrollment, >75% of participants in all groups had plasma 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL, and >85% of participants across groups were anemic. In the 500,000-IU D₃ group, hemoglobin concentrations increased significantly over time (P_{group × time} = .01) compared with placebo but did not change in the 250,000-IU D₃ group (P_{group × time} = 0.59). Hepcidin concentrations decreased acutely in the 500,000-IU D₃ group relative to placebo after 1 week (P = .007). Hepcidin did not change significantly in the 250,000-IU D₃ group.

Conclusion: In these critically ill adults, treatment with 500,000 IU D₃ was associated with increased hemoglobin concentrations over time and acutely reduced serum hepcidin concentrations. These findings suggest that high-dose vitamin D may improve iron metabolism in critical illness and should be confirmed in larger studies.

Keywords: anemia; critical illness; hemoglobin; hepcidin; vitamin D.

Figure 1

Geometric mean hemoglobin concentrations with corresponding 95% confidence intervals in critically ill adults. Hemoglobin concentrations are reported across time and by treatment group. Hemoglobin concentrations increased significantly over time in the group that received 500,000 IU D₃ compared to the placebo group; there was no significant change in the 250,000 IU D₃ group. By three weeks, hemoglobin concentrations in the 500,000 IU D₃ group differed significantly from the placebo group; there were no statistically significant differences between groups at other time points. *P<0.05; group*time, group-by-time interaction. Sample sizes in the placebo, 250,000 IU D₃, and 500,000 IU D₃ groups, respectively: enrollment n = 10, 9, 11; 1 week n = 9, 9, 9; 2 weeks n = 8, 6, 5; 3 weeks n = 5, 4, 2; 4 weeks n = 2, 2, 1.

Figure 2

Geometric mean hepcidin concentrations with corresponding 95% confidence intervals in critically ill adults. Hepcidin concentrations are reported across time and by treatment group. There were no significant differences over time in hepcidin concentrations in either vitamin D-treated group relative to placebo. Hepcidin concentrations in the 500,000 IU D₃ group differed significantly from the placebo group one week after dosing; there were no statistically significant differences between groups at other time points. *P<0.05; group*time, group-by-time interaction. Sample sizes in the placebo, 250,000 IU D₃, and 500,000 IU D₃ groups, respectively: enrollment n = 10, 9, 11; 1 week n = 9, 6, 9; 2 weeks n = 8, 6, 5; 3 weeks n = 4, 4, 2.