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N Engl J Med. 2019 Dec 26;381(26):2529-2540. doi: 10.1056/NEJMoa1911124. Epub 2019 Dec 11.

Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients.

Collaborators (269)

Steingrub JS, Tidswell M, Kozikowski LA, De Souzaa L, Kardos C, Hill NS, Bacong V, Shweish O, Chweich H, Garpestad E, Hou P, Baron R, Massaro A, Fredenburgh L, Aisiku I, Seethala R, Skubic J, Isrealyan A, Precopio L, Fawcett M, Pajak S, Riker R, MacLeod A, May T, Van der Kloot T, Seder D, Talmor D, Shapiro N, Banner-Goodspeed V, Hayes S, Raddell T, Hibbert KA, Filbin M, Brait K, Stathas M, Rizzo C, Arsenault PA, Sigel P, Miru D, Jones AE, Spurzem JR, Puskarich MA, McDonald J, Kirby M, Matthay M, Liu K, Calfee CS, Gotts J, Ni A, Vessel K, Belzer A, Almarsi E, Blaauw J, Hughes A, Sousa K, Armenian P, Albertson TE, Morrissey B, Pearson SJ, Juarez M, Chenoweth J, Levitt J, Wilson J, Rogers A, Vojnik R, Roque J, Hendey GW, Chang SY, Qadir N, Garber B, Phan C, Ginde A, Moss M, Finck L, Perman S, Hoffman J, Mayer K, Douglas I, Haukoos J, Hiller T, Lyle C, Oakes J, Caruso E, Schmidt M, Gravitz S, Van Pelt D, McKeehan J, Higgins C, Finigan J, Paterson R, Lyn-Kew K, Howell M, Hyzy RC, Park PK, Nelson K, Co IN, McSparron JI, Gunnerson KJ, Chen T, Hanna S, Olbrich N, Rivers EP, Gardner Gray J, DiGiovine B, Kaur Gill J, Cook A, Chaudry K, Day J, Rubino S, Jaehne AK, Pflaum J, Hurst G, Swiderek J, Jayaprakesh N, Ng Gong M, Hope A, Gummadi S, Richardson LD, Acquah S, Andreae M, Mathews K, Goel N, Clesca C, Massenburg NS, Chen JT, Lopez B, Aboodi M, Hite RD, Duggal A, Mace S, Hastings A, Mehkri O, Stoianoff S, Terndrup TE, Exline MC, Englert JA, Karow SC, Garmatter J, Hudock K, Adeoye O, Norton D, Studer A, Gorder K, Courtney DM, Rowland M, Hough CL, Robinson BRH, Johnson NJ, Gundel S, Katsandres S, Henning D, Poon T, Dean S, Cardey J, Ungar A, O'Mahony DS, Wallick J, Khan A, Schreiber M, Kea B, Haq E, Krol O, Angus DC, Yealy DM, Huang DT, McVerry BJ, Gacka C, Yanta J, Abesamis M, McGarry SL, Schooler J, Wojnar M, Sinz E, Zacko C, Campbell N, Files DC, Miller C, Gibbs K, Flores L, Koehler L, Enfield K, Sochor M, Marshall M, Simpson A, Sherwood D, de Wit M, Miller S, Syed A, Mason J, Hamman S, Morris P, Humphries R, Sturgill J, Montgomery-Yates A, Cassity EP, Brown SM, Bledsoe J, Peltan I, Lanspa M, Brown K, Armbruster B, Montgomery Q, Aston V, Hirshberg E, Harris D, Woodard W, Kumar N, Merrill M, Nielson D, Daw A, Harris E, Paine R, Plante A, Middleton E, Self WH, Rice TW, Semler MW, Baughman A, Hays M, Miller K, Mogan S, Janz DR, Lauto P, Moore MM, deBoisblanc BP, Hunt JP, Carson SS, Platts-Mills TF, Quackenbush EB, Chronowski KJ, Rice C, Limkakeng AT Jr, Griffin SM, Leahy JC, Cox C, Eppensteiner J, Schoenfeld DA, Thompson BT, Lee KT, Ulysse C, Oldmixon CF, Ringwood NJ, Pedrin JR, Morse RE, Hayden D, Brower RG, Bienstock K, Blaisdell CJ, Freemer M, Harabin AL, Kunz L, Reineck LA, Ghofrani P, Waclawiw MA, Weinmann G, Morrison LJ, Cairns CB, Gillespie MN, Kryscio RJ, Scales D, Parsons P, Christie JD, Hall JR, Horton NJ, Kline JA, Levy M, Siegel M, Stiell I, Zoloth LS.

Author information

The affiliations of the members of the writing committee are as follows: the Department of Emergency Medicine, University of Colorado School of Medicine, Aurora (A.A.G., L.F.); the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore (R.G.B.); the Department of Emergency Medicine, Ohio State University, Columbus (J.M.C.); the Departments of Anesthesia, Critical Care, and Pain Medicine (V.M.B.-G., D.T.) and Emergency Medicine (N.I.S.), Beth Israel Deaconess Medical Center, and the Biostatistics Center (D.H.) and the Department of Medicine (N.R., B.T.T.), Massachusetts General Hospital - all in Boston; the Department of Medicine, Intermountain Medical Center and the University of Utah, Salt Lake City (C.K.G.); the Department of Medicine, University of Washington, Seattle (C.L.H.); the Departments of Medicine (R.C.H.) and Surgery (P.K.P.), University of Michigan, Ann Arbor; the Department of Emergency Medicine and Surgery, Henry Ford Hospital, Detroit (E.P.R.); the Department of Medicine, Oregon Health and Science University, Portland (A.K.); the Department of Medicine, Stanford University, Palo Alto, CA (J.E.L.); the Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville (W.H.S.); and the Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh (D.M.Y.).



Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study.


We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality.


A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P = 0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality.


Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET number, NCT03096314.).


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