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


      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.


      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).


      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; No.: NCT03733418; URL:

      Key Words


      ADL (activities of daily living), D-KEFS (Delis-Kaplan Executive Function System), IADL (instrumental activities of daily living), IQR (interquartile range), LTCI (long-term cognitive impairment), RBANS (Repeatable Battery for the Assessment of Neuropsychological Status), SOFA (Sequential Organ Failure Assessment), VIOLET (Vitamin D to Improve Outcomes by Leveraging Early Treatment), VIOLET-BUD (Vitamin D to Improve Outcomes by Leveraging Early Treatment—Long-Term Brain Outcomes in Vitamin D Deficient Patients)
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        • Pandharipande P.P.
        • Girard T.D.
        • Jackson J.C.
        • et al.
        Long-term cognitive impairment after critical illness.
        N Engl J Med. 2013; 369: 1306-1316
        • Norman B.C.
        • Jackson J.C.
        • Graves J.A.
        • et al.
        Employment outcomes after critical illness: an analysis of the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors cohort.
        Crit Care Med. 2016; 44: 2003-2009
        • Simone M.J.
        • Tan Z.S.
        The role of inflammation in the pathogenesis of delirium and dementia in older adults: a review.
        CNS Neurosci Ther. 2011; 17: 506-513
        • D’Ambrosio D.
        • Cippitelli M.
        • Cocciolo M.G.
        • et al.
        Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene.
        J Clin Invest. 1998; 101: 252-262
        • Muller K.
        • Haahr P.M.
        • Diamant M.
        • Rieneck K.
        • Kharazmi A.
        • Bendtzen K.
        1,25-Dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level.
        Cytokine. 1992; 4: 506-512
        • Schleithoff S.S.
        • Zittermann A.
        • Tenderich G.
        • Berthold H.K.
        • Stehle P.
        • Koerfer R.
        Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.
        Am J Clin Nutr. 2006; 83: 754-759
        • Balabanova S.
        • Richter H.P.
        • Antoniadis G.
        • et al.
        25-Hydroxyvitamin D, 24, 25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D in human cerebrospinal fluid.
        Klin Wochenschr. 1984; 62: 1086-1090
        • Lefebvre d’Hellencourt C.
        • Montero-Menei C.N.
        • Bernard R.
        • Couez D.
        Vitamin D3 inhibits proinflammatory cytokines and nitric oxide production by the EOC13 microglial cell line.
        J Neurosci Res. 2003; 71: 575-582
        • Evans C.S.
        • Self W.
        • Ginde A.A.
        • Chandrasekhar R.
        • Ely E.W.
        • Han J.H.
        Vitamin D deficiency and long-term cognitive impairment among older adult emergency department patients.
        West J Emerg Med. 2019; 20: 926-930
        • Annweiler C.
        • Allali G.
        • Allain P.
        • et al.
        Vitamin D and cognitive performance in adults: a systematic review.
        Eur J Neurol. 2009; 16: 1083-1089
        • Balion C.
        • Griffith L.E.
        • Strifler L.
        • et al.
        Vitamin D, cognition, and dementia: a systematic review and meta-analysis.
        Neurology. 2012; 79: 1397-1405
        • Annweiler C.
        • Fantino B.
        • Gautier J.
        • Beaudenon M.
        • Thiery S.
        • Beauchet O.
        Cognitive effects of vitamin D supplementation in older outpatients visiting a memory clinic: a pre-post study.
        J Am Geriatr Soc. 2012; 60: 793-795
        • Ginde A.A.
        • Brower R.G.
        • Caterino J.M.
        • et al.
        Early high-dose vitamin D3 for critically ill, vitamin D-deficient patients.
        N Engl J Med. 2019; 381: 2529-2540
        • Amrein K.
        • Schnedl C.
        • Holl A.
        • et al.
        Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial.
        JAMA. 2014; 312: 1520-1530
        • Randolph C.
        • Tierney M.C.
        • Mohr E.
        • Chase T.N.
        The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): preliminary clinical validity.
        J Clin Exp Neuropsychol. 1998; 20: 310-319
        • Duff K.
        • Hobson V.L.
        • Beglinger L.J.
        • O’Bryant S.E.
        Diagnostic accuracy of the RBANS in mild cognitive impairment: limitations on assessing milder impairments.
        Arch Clin Neuropsychol. 2010; 25: 429-441
        • Duff K.
        • Humphreys Clark J.D.
        • O’Bryant S.E.
        • Mold J.W.
        • Schiffer R.B.
        • Sutker P.B.
        Utility of the RBANS in detecting cognitive impairment associated with Alzheimer’s disease: sensitivity, specificity, and positive and negative predictive powers.
        Arch Clin Neuropsychol. 2008; 23: 603-612
        • Hobson V.L.
        • Hall J.R.
        • Humphreys-Clark J.D.
        • Schrimsher G.W.
        • O’Bryant S.E.
        Identifying functional impairment with scores from the repeatable battery for the assessment of neuropsychological status (RBANS).
        Int J Geriatr Psychiatry. 2010; 25: 525-530
        • McKay C.
        • Casey J.E.
        • Wertheimer J.
        • Fichtenberg N.L.
        Reliability and validity of the RBANS in a traumatic brain injured sample.
        Arch Clin Neuropsychol. 2007; 22: 91-98
        • Latzman R.D.
        • Markon K.E.
        The factor structure and age-related factorial invariance of the Delis-Kaplan Executive Function System (D-KEFS).
        Assessment. 2010; 17: 172-184
        • Galusha-Glasscock J.M.
        • Horton D.K.
        • Weiner M.F.
        • Cullum C.M.
        Video Teleconference administration of the Repeatable Battery for the Assessment of Neuropsychological Status.
        Arch Clin Neuropsychol. 2016; 31: 8-11
        • Han J.H.
        • Collar E.M.
        • Lassen-Greene C.
        • Self W.H.
        • Langford R.W.
        • Jackson J.C.
        Feasibility of videophone-assisted neuropsychological testing for intensive care unit survivors.
        Am J Crit Care. 2020; 29: 398-402
        • Needham D.M.
        • Colantuoni E.
        • Mendez-Tellez P.A.
        • et al.
        Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study.
        BMJ. 2012; 344: e2124
        • Barona A.
        • Reynolds C.R.
        • Chastain R.
        A demographically based index of premorbid intelligence for the WAIS-R.
        J Consult Clin Psychol. 1984; 35: 341-345
        • Charlson M.E.
        • Pompei P.
        • Ales K.L.
        • MacKenzie C.R.
        A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
        J Chron Dis. 1987; 40: 373-383
        • Hernandez A.V.
        • Steyerberg E.W.
        • Habbema J.D.
        Covariate adjustment in randomized controlled trials with dichotomous outcomes increases statistical power and reduces sample size requirements.
        J Clin Epidemiol. 2004; 57: 454-460
        • White H.
        A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity.
        Econometrica. 1980; 48: 817-838
        • Liu Q.
        • Shepherd B.E.
        • Li C.
        • Harrell Jr., F.E.
        Modeling continuous response variables using ordinal regression.
        Stat Med. 2017; 36: 4316-4335
        • Copay A.G.
        • Subach B.R.
        • Glassman S.D.
        • Polly Jr., D.W.
        • Schuler T.C.
        Understanding the minimum clinically important difference: a review of concepts and methods.
        Spine J. 2007; 7: 541-546
        • Phillips R.
        • Qi G.
        • Collinson S.L.
        • et al.
        The minimum clinically important difference in the repeatable battery for the assessment of neuropsychological status.
        Clin Neuropsychol. 2015; 29: 905-923
        • Annweiler C.
        • Schott A.M.
        • Rolland Y.
        • Blain H.
        • Herrmann F.R.
        • Beauchet O.
        Dietary intake of vitamin D and cognition in older women: a large population-based study.
        Neurology. 2010; 75: 1810-1816
        • Annweiler C.
        • Rolland Y.
        • Schott A.M.
        • et al.
        Higher vitamin D dietary intake is associated with lower risk of Alzheimer’s disease: a 7-year follow-up.
        J Gerontol. 2012; 67: 1205-1211
        • Amrein K.
        • Sourij H.
        • Wagner G.
        • et al.
        Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double-blind, placebo-controlled pilot study.
        Crit Care. 2011; 15: R104
        • Munro Cullum C.
        • Hynan L.S.
        • Grosch M.
        • Parikh M.
        • Weiner M.F.
        Teleneuropsychology: evidence for video teleconference-based neuropsychological assessment.
        J Int Neuropsychol Soc. 2014; 20: 1028-1033
        • Wadsworth H.E.
        • Galusha-Glasscock J.M.
        • Womack K.B.
        • et al.
        Remote neuropsychological assessment in rural American Indians with and without cognitive impairment.
        Arch Clin Neuropsychol. 2016; 31: 420-425
        • Mahoney F.I.
        • Barthel D.W.
        Functional evaluation: the Barthel Index.
        Md State Med J. 1965; 14: 61-65
        • Pfeffer R.I.
        • Kurosaki T.T.
        • Harrah Jr., C.H.
        • Chance J.M.
        • Filos S.
        Measurement of functional activities in older adults in the community.
        J Gerontol. 1982; 37: 323-329
        • Needham D.M.
        • Sepulveda K.A.
        • Dinglas V.D.
        • et al.
        Core outcome measures for clinical research in acute respiratory failure survivors. An International Modified Delphi Consensus Study.
        Am J Respir Crit Care Med. 2017; 196: 1122-1130
        • Inouye S.K.
        • Marcantonio E.R.
        • Kosar C.M.
        • et al.
        The short-term and long-term relationship between delirium and cognitive trajectory in older surgical patients.
        Alzheimers Dement. 2016; 12: 766-775