High-Dose Vitamin D Shows No Benefit in the Critically Ill

Nancy A. Melville

December 12, 2019

Critically ill patients who are vitamin D deficient do not seem to gain any benefit from the administration of high-dose vitamin D in the intensive care unit, results from a phase 3 randomized trial indicate.

"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," concludes the National Heart, Lung, and Blood Institute (NHLBI) Prevention and Early Treatment of Acute Lung Injury (PETAL) Network, which conducted the study.

The findings were published online December 11 in the New England Journal of Medicine.

With studies linking vitamin D deficiency to morbidity as well as mortality in critical illness, supplementation with high doses of vitamin D has gained interest as potentially having some benefit, and smaller studies have suggested some reductions in mortality with vitamin D administration among critically ill patients.

Over 1000 Critically Ill Patients Randomized

To evaluate the issue in a large population, the PETAL Network conducted the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, enrolling critically ill patients who were at a high risk of death at 44 US hospitals.

Of those patients, 1078 had vitamin D deficiency confirmed on subsequent liquid chromatography–tandem mass spectrometry testing and were included in the primary analysis.

Patients were randomized within 12 hours of the decision to admit to the intensive care unit (ICU) from the emergency department, hospital ward, operating room, or outside facility to receive a single enteral dose of 540,000 IU of vitamin D3 or matched placebo; 1059 patients received the assigned treatment.

At day 3 following administration, the mean level of 25-hydroxyvitamin D in the supplement group increased to 46.9 ± 23.2 ng/mL and the level in the placebo group was 11.4 ± 5.6 ng/mL.

The 90-day mortality rates in the primary analysis population were 23.5% in the vitamin D group (125 of 531 patients died) and 20.6% in the placebo group (109 of 528 patients died); the difference was not significant (P = .26).

The data and safety monitoring board recommended the trial be stopped at the first interim analysis on the basis of a probability of less than 2% that vitamin D treatment would be found superior to placebo in the full trial enrolment population.

The two groups showed no significant differences in any other secondary clinical, physiological, or safety endpoints, such as length of hospital stay, ventilator-free days, or change in the five-level EuroQol 5 dimensions (EQ-5D-5L) score.

Importantly, predefined subgroups of interest, including those with more severe vitamin D deficiency and specific acute risk factors for death, also gained no benefit from vitamin D supplementation.

Early Testing for, or Treatment of, Vitamin D Deficiency Not Supported

Conversely — and unexpectedly — a higher mortality rate was in fact observed in the vitamin D supplemented patients whose illnesses had infectious causes, and those who had acute respiratory distress syndrome prior to randomization.

Several factors could explain those findings, the authors note.

"This observation may reflect differences between the use of vitamin D for prevention in previous studies and the use of vitamin D as treatment during acute illness in the present trial, but it also may be the result of chance," they say.

In the previous phase 2 VITdAL-ICU study published in 2014, 475 vitamin D–deficient, critically ill patients had lower mortality with supplementation; however, the difference was not significant compared with placebo at 28 days (21.9% vs 28.6%; P = .14) and at 6 months (35.0% vs 42.9%; P = .09).

The authors of the current study note that there are important differences between their trial and VITdAL-ICU, such as the fact that patients in the new trial were enrolled earlier in their critical illness and had typical medical ICU illnesses, such as pneumonia, sepsis, shock, or respiratory failure, whereas most patients in the phase 2 trial were surgical or neurologic ICU patients.

And in the earlier trial 99% of patients were white, whereas the new study was racially diverse and representative of the US population.

"Given known differences in vitamin D metabolism and response genes according to race and ethnic group, such differences may affect the results," the authors write.

They conclude, however, that "the results of the present trial do not support early testing for, or treatment of, vitamin D deficiency in critically ill patients."

N Engl J Med. Published online December 11, 2019. Abstract

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