Effect of Cholecalciferol Supplementation on Vitamin D Status and Cathelicidin Levels in Sepsis: A Randomized, Placebo-Controlled Trial

Abstract

Objectives: To compare changes in vitamin D status and cathelicidin (LL-37) levels in septic ICU patients treated with placebo versus cholecalciferol.

Design: Randomized, placebo-controlled, trial.

Setting: Medical and surgical ICUs of a single teaching hospital in Boston, MA.

Patients: Thirty adult ICU patients.

Interventions: Placebo (n = 10) versus 200,000 IU cholecalciferol (n = 10) versus 400,000 IU cholecalciferol (n = 10), within 24 hours of new-onset severe sepsis or septic shock.

Measurements and main results: Blood samples were obtained at baseline (day 1) and on days 3, 5, and 7, to assess total 25-hydroxyvitamin D, as well as vitamin D-binding protein and albumin to calculate bioavailable 25-hydroxyvitamin D. Plasma LL-37 and high-sensitivity C-reactive protein levels were also measured. At baseline, median (interquartile range) plasma 25-hydroxyvitamin D was 17 ng/mL (13-22 ng/mL) and peaked by day 5 in both intervention groups. Groups were compared using Kruskal-Wallis tests. Relative to baseline, on day 5, median change in biomarkers for placebo, 200,000 IU cholecalciferol, and 400,000 IU cholecalciferol groups, respectively, were as follows: 1) total 25-hydroxyvitamin D, 3% (-3% to 8%), 49% (30-82%), and 69% (55-106%) (p < 0.001); 2) bioavailable 25-hydroxyvitamin D, 4% (-8% to 7%), 45% (40-70%), and 96% (58-136%) (p < 0.01); and 3) LL-37: -17% (-9% to -23%), 4% (-10% to 14%), and 30% (23-48%) (p = 0.04). Change in high-sensitivity C-reactive protein levels did not differ between groups. A positive correlation was observed between bioavailable 25-hydroxyvitamin D and LL-37 (Spearman ρ = 0.44; p = 0.03) but not for total 25-hydroxyvitamin D and LL-37.

Conclusions: High-dose cholecalciferol supplementation rapidly and safely improves 25-hydroxyvitamin D and bioavailable 25-hydroxyvitamin D levels in patients with severe sepsis or septic shock. Changes in bioavailable 25-hydroxyvitamin D are associated with concomitant increases in circulating LL-37 levels. Larger trials are needed to verify these findings and to assess whether optimizing vitamin D status improves sepsis-related clinical outcomes.

Figures

Figure 1

Median (with interquartile ranges) change in 25-hydroxyvitamin D levels on days 3, 5, and 7 relative to baseline (day 1): Peak plasma levels are achieved by day 5 in both the 200,000 IU cholecalciferol and 400,000 IU cholecalciferol groups.

Figure 2

Change in biomarker levels on day 5 expressed as a percentage of baseline levels (day 1). Significant differences in 25-hydroxyvitamin D (A), bioavailable 25-hydroxyvitamin D (B), and cathelicidin (C) levels were observed between groups. No difference was observed in high-sensitivity C-reactive protein (D) levels.

Figure 3

Change in pro-inflammatory cytokines on day 5 expressed as a percentage of baseline level (day 1). Significant differences in interleukin-1β (A) and interleukin-6 (B) levels were observed between groups. A trend towards significant difference in interferon-γ (D) was also observed between groups. No difference was observed in tumor necrosis factor-α (C) levels between groups.

Figure 4

Change in anti-inflammatory cytokines on day 5 expressed as a percentage of baseline level (day1). A trend towards significant difference in interleukin-10 (B) levels was observed between groups. No difference was observed in interleukin-4 (A) levels between groups.