Trying to identify who may benefit most from future vitamin D intervention trials: a post hoc analysis from the VITDAL-ICU study excluding the early deaths

Research output: Contribution to journalArticlepeer-review


  • Gennaro Martucci
  • Dayre McNally
  • Paul Zajic
  • Fabio Tuzzolino
  • Antonio Arcadipane
  • Kenneth B Christopher
  • Harald Dobnig
  • Karin Amrein

Colleges, School and Institutes

External organisations

  • Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Palermo, Italy.
  • Faculty of Medicine, Division of Critical Care, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada.
  • Critical Care, Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.
  • Division of General Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria.
  • Research Office, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Palermo, Italy.
  • Brigham and Women's Hospital, Harvard Medical School, Renal Division, Boston, MA, USA.
  • Thyroid Endocrinology Osteoporosis Institute Dobnig, Graz, Austria.
  • Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, A-8036, Graz, Austria.


BACKGROUND: Vitamin D supplementation has shown promise for reducing mortality in the intensive care setting. As a steroid prohormone with pleiotropic effects, there may be a lag between administration and observing clinical benefit. This secondary analysis of the VITdAL-ICU study sought to explore whether the effect size of vitamin D on mortality was different when study participants who died or were discharged early were excluded.

METHODS: The VITdAL-ICU study was a randomized, placebo-controlled trial in critically ill adults who received placebo or 540,000 IU cholecalciferol followed by monthly supplementation. The effect of vitamin D on 28-day mortality was evaluated after exclusion of participants who died or were discharged within 7 days from study drug administration, according to vitamin D concentrations on day 3, using a bivariate analysis adjusted for confounders and in a stepwise multiple analysis.

RESULTS: Of 475 study participants, 65 died or were discharged within the first 7 days. In the remaining 410 patients, vitamin D supplementation was associated with a reduction in 28-day mortality [OR 0.58 (95% CI 0.35-0.97) p value = 0.035]. The effect on mortality was not significant after adjusting for age, severity scores, female gender, chronic liver and kidney disease, COPD, diagnosis of the tumor, mechanical ventilation, and vasopressors at enrollment (all p > 0.05). In a multiple model, the mortality reduction by vitamin D supplementation did not remain independently significant [OR 0.61 (95% CI 0.35-1.05) p = 0.075]. Vitamin D metabolite response, in the treatment group, demonstrated that survivors at 28 days, had higher levels of 25-hydroxyvitamin D (34.4 vs 25.4 ng/ml, p = 0.010) and 1,25-dihydroxyvitamin D (107.6 vs 70.3 pg/ml, p = 0.049) on day 3. The increase of plasma metabolites after vitamin D oral supplementation, independent of the baseline value, was associated with lower odds of death [OR 0.48 (95% CI 0.27-0.87) p value = 0.016].

CONCLUSIONS: High-dose vitamin D3 supplementation was associated with a reduction of 28-day mortality in a mixed population of critically ill adults with vitamin D deficiency when excluding patients who died or were discharged within 7 days after study inclusion. However, this survival benefit was not independently confirmed when adjusted for other factors strongly associated with mortality.


Original languageEnglish
Pages (from-to)200
JournalCritical care (London, England)
Issue number1
Publication statusPublished - 4 Jun 2019


  • Aged, Aged, 80 and over, Critical Illness/mortality, Double-Blind Method, Female, Humans, Intensive Care Units/organization & administration, Logistic Models, Male, Middle Aged, Mortality/trends, Placebos, Survival Analysis, Vitamin D/blood, Vitamin D Deficiency/blood, Vitamins/pharmacology