Sex-Specific Metabolomics and Response to High Dose Vitamin D in Critical Illness: Post-Hoc Analyses of the VITdAL-ICU Trial

Abstract

Abstract (Sex-Specific Critical Illness Metabolomics: A Post-Hoc Analysis of the VITdAL-ICU Trial) Rationale: It is unclear if the metabolic response to early critical illness differs in women and men. Objectives: To determine the sex-specific metabolomic response early in the course of critical illness. Methods: We performed a post-hoc metabolomics study of the VITdAL-ICU randomized, double-blind, placebo-controlled trial. Trial patients from Medical and Surgical Intensive Care Units at a tertiary university hospital with 25-hydroxyvitamin D level ≤ 20 ng/mL received either high dose oral vitamin D3 (540,000 IU) or placebo. We performed an analysis of 578 metabolites in 1215 plasma samples from 428 subjects at randomization (day 0), day 3 and 7. Using mixed-effects modeling, we studied sex-specific changes in individual metabolites over time adjusted for age, Simplified Acute Physiology Score II, admission diagnosis, baseline 25-hydroxyvitamin D level, and 25-hydroxyvitamin D response to intervention. We employed Gaussian graphical modeling to identify groups of sex-specific metabolites that are functionally co-regulated. Measurements and Main Results: 35% of subjects were women. In women, multiple members of the sphingomyelin and lysophospholipid metabolite classes had significantly positive Bonferroni corrected associations over time compared to men. Further, multiple representatives of the acylcarnitine, androgenic steroids, bile acid, nucleotide and amino acid metabolite classes had significantly negative Bonferroni corrected associations over time compared to men. Gaussian graphical model analyses revealed seven sex-specific functional modules at day 3 and seven at day 7. Conclusions: Robust coordinated sex-specific metabolite differences are present early in critical illness. This work increases our understanding of the sex-specific differences in the metabolic response to critical illness. Abstract (Sex-Specific Response to High-Dose Vitamin D in Critical Illness: A Post-Hoc Analysis of the VITdAL-ICU Trial) Rationale: It is unclear if the metabolic response to high dose vitamin D in critical illness differs in women and men. Objectives: To determine the sex-specific metabolomic response early in the course of critical illness. Methods: We performed a post-hoc metabolomics study of the VITdAL-ICU randomized double-blind, placebo-controlled trial. Trial patients from Medical and Surgical Intensive Care Units at a tertiary university hospital with 25-hydroxyvitamin D level ≤ 20 ng/mL received either high dose oral vitamin D3 (540,000 IU) or placebo. We performed an analysis of 578 metabolites in 1215 plasma samples from 428 subjects at randomization (day 0), day 3 and 7. Using mixed-effects modeling, we studied the association between sex-specific changes in individual metabolites over time and 25-hydroxyvitamin D response to intervention adjusted for age, Simplified Acute Physiology Score II, admission diagnosis and baseline 25-hydroxyvitamin D level. Additionally, we determined the sex-specific pharmacokinetics of high dose oral vitamin D. Measurements and Main Results: 35% of subjects were women and 27% responded to high dose vitamin D3, with an increase of ≥ 15 ng/ml 25-hydroxyvitamin D by day 3. Compared with women, the pharmacokinetic parameters of 25(OH)D using non-compartmental analysis showed significantly higher normalized AUC0-7 in men. At day 0, sex-specific metabolomic differences in patients who do or do not respond to vitamin D3 are present. In the mixed-effects analysis, a sex-specific metabolomic response to vitamin D3 is associated with differential metabolite patterns over time. Specifically, women have higher and more significant Bonferroni corrected increases in circulating free fatty acids and long chain acylcarnitines than men in response to an increase of ≥ 15 ng/ml 25-hydroxyvitamin D by day 3. Conclusions: Response to high dose oral vitamin D3 is sex specific. Robust coordinated sex-specific metabolite differences are present with an increase in 25-hydroxyvitamin D by day 3.