Effect of Early High-Dose Vitamin D3 Repletion on Cognitive Outcomes in Critically Ill Adults

Chest. 2021 Sep;160(3):909-918. doi: 10.1016/j.chest.2021.03.046. Epub 2021 Apr 2.


Background: Long-term cognitive impairment frequently occurs after critical illness; no treatments are known to improve long-term cognition.

Research question: Does a single high-dose (540,000 International Units) enteral treatment of vitamin D3 given shortly after hospital admission in critically ill patients who are vitamin D deficient improve long-term global cognition or executive function?

Study design and methods: This study evaluated long-term cognitive outcomes among patients enrolled in a multicenter, blinded, randomized clinical trial comparing vitamin D3 treatment vs placebo in critically ill adults with vitamin D deficiency. Global cognition was measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Executive function was measured with a composite score derived from three Delis-Kaplan Executive Function System subscales. Outcomes were assessed at a median of 443 days (interquartile range, 390-482 days) after randomization and were compared using multivariate proportional odds regression. Adjusted ORs of > 1.0 would indicate better outcomes in the vitamin D3 group compared with the placebo group.

Results: Ninety-five patients were enrolled, including 47 patients randomized to vitamin D3 treatment and 48 patients randomized to placebo. The adjusted median RBANS score at follow-up was 79.6 (95% CI, 73.0-84.0) in the vitamin D3 group and 82.1 (95% CI, 74.7-84.6) in the placebo group (adjusted OR, 0.83; 95% CI, 0.50-1.38). The adjusted median executive function composite scores were 8.1 (95% CI, 6.8-9.0) and 8.7 (95% CI, 7.4-9.3), respectively (adjusted OR, 0.72; 95% CI, 0.36-1.42).

Interpretation: In vitamin D-deficient, critically-ill adults, a large dose of enteral vitamin D3 did not improve long-term global cognition or executive function.

Trial registry: ClinicalTrials.gov; No.: NCT03733418; URL: www.clinicaltrials.gov.

Keywords: ICU; executive function; global cognition; vitamin D.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cholecalciferol / administration & dosage*
  • Cognition / drug effects*
  • Cognitive Dysfunction* / diagnosis
  • Cognitive Dysfunction* / drug therapy
  • Cognitive Dysfunction* / etiology
  • Critical Illness* / psychology
  • Critical Illness* / rehabilitation
  • Executive Function / drug effects*
  • Female
  • Humans
  • Long Term Adverse Effects / diagnosis
  • Long Term Adverse Effects / drug therapy*
  • Long Term Adverse Effects / etiology
  • Long Term Adverse Effects / psychology
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Pulse Therapy, Drug / methods
  • Treatment Outcome
  • Vitamin D Deficiency* / drug therapy
  • Vitamin D Deficiency* / psychology
  • Vitamins / administration & dosage


  • Vitamins
  • Cholecalciferol

Associated data

  • ClinicalTrials.gov/NCT03733418