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Vitamin D supplementation brought no measurable benefits to vitamin D-deficient critically ill patients, in a large randomized trial published in the New England Journal of Medicine.
Vitamin D supplementation has long been hoped for as a potential lifesaving therapy in critical illness. Many critically ill patients are vitamin D deficient, and deficiency increases the risk for poor outcomes and death. In the VITdAL-ICU randomized trial, more patients receiving extra vitamin initially survived, although the mortality benefit disappeared within months.
For the VIOLET trial, researchers screened 2,624 patients being admitted to ICUs at 44 U.S. hospitals for vitamin D deficiency, ultimately randomizing 1,078 vitamin D deficient patients to quickly receive a single 540,000 IU enteral dose of vitamin D3 or placebo (blinded).
Patients were very ill; most had pneumonia, sepsis, need for mechanical ventilation or vasopressors, and were at high risk for acute respiratory distress syndrome (ARDS).
The trial was conducted and funded through the National Heart, Lung, and Blood Institute (NHLBI) Prevention and Early Treatment of Acute Lung Injury (PETAL) Network.
Vitamin D had no detectable beneficial effect: there were no differences in 90 day mortality, the primary outcome (23.5% in vitamin D supplemented patients, 20.6% with placebo), length of stay, or days of mechanical ventilation.
There was no suggestion of a dose-response curve. The most severely vitamin D-deficient patients did not come closer to experiencing a benefit from supplementation than the less-deficient patients.
The trial was stopped for futility after an interim statistical analysis, before reaching the original enrollment target of ~3000 patients.
The VIOLET trial extinguishes some of the last flames of hopeful enthusiasm for vitamin D supplementation as a therapeutic target in critical illness and respiratory disease. Vitamin D supplementation was hoped to possibly reduce asthma exacerbations in vitamin D deficient patients with asthma, but the VIDA trial showed no benefit.
Vitamin D production and metabolism are altered substantially during illness, frequently causing levels to fall below the lower limit of what experts have defined as normal. It's not known for sure that this is harmful in itself. Thus the categorization of ill patients as "deficient" in vitamin D is itself debatable.
But what about the correlations between vitamin D deficiency and poor outcomes in critical illness, and in asthma? For many patients the low vitamin D levels may simply be a signal of the severity of disease, not directly influencing the pathophysiology of their illness. If you think fixing every abnormal lab value is a treatment pathway, you've fallen victim to the normalization fallacy.