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

The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network

Setting: The study was conducted The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network from April 2017 through July 2018 at 44 U.S. hospitals.

Design: 1:1 randomized controlled study, Vit D vs. placebo, using a central electronic system, stratified by site

Inclusion: Adults were screened for Vitamin D deficiency by the hospital lab or by a POC test; with a lower cut-off level of 25OH <20 ng/mL. These patients were randomized to one of the study groups. subsequently they underwent confirmation of deficiency by liquid

The Primary analysis based on vitamin D deficiency by the liquid chromatography test.  Patients had risk factors for death or lung injury and admitted to ICU for pneumonia, sepsis, shock, mechanical ventilation for acute respiratory failure, aspiration, smoke inhalation, pancreatitis, or lung contusion.

Exclusion: enteral drug administration not possible, a history of kidney stones, hypercalcemia, informed consent not obtained in a timely manner

Intervention: Enrollment within 12 hours of ICU admission.  540,000 IU of vitamin D3 in liquid form, administered within 2 hours after randomization.

Control: Matched placebo in liquid form. Vitamin D testing or additional vitamin D supplementation within 1 month after administration of vitamin D or placebo was discouraged.

Sample size: Calculated based on a 90-day mortality reduction from 20% in the placebo to 15% in the vitamin D group. Assuming vitamin D deficiency would be present in 80% of the patients. Thus, a sample size of 3000 patients would provide 87% power.

15924 were assessed for eligibility

531 (7 lost) vs. 528 (12 lost) after loss to follow-up

528 Were included in the analysis of the primary end point

Results

The study was stopped for futility after the first interim analysis.

SOFA score: 5.6; 32% patients received ventilation; 32% received vasopressors; no difference between groups. Well-matched at baseline.

Primary outcome:

90-d all-cause mortality at any location: 125/531 (23.5%) vs. 109/528 (20.6%) (p=0.26)

The observed mortality was higher in the vitamin D group than in the placebo group for several subgroups: patients with sepsis or infection in the primary analysis population and pre- hospital facility residence, pneumonia, infection, and pre-randomization acute respiratory distress syndrome in the screened-deficient population.

Secondary outcomes:

28-d mortality (any location): 17.3 vs 13.1%

Hospital length of until day 90: 9.0 vs. 9.9 days

Proportions of patients alive and at home at day 90 (at previous level): 65.9% vs. 65.6%

Ventilator-free until day 28: 21.3 vs. 22.1 days

Time to death until day 90

Quality of life until day 90

Secondary physiological end points:

Post-randomization mechanical ventilation: 10.7 vs. 8.2%

Lowest P/F ratio until day 7: 179.8 vs. 185.8

Acute respiratory distress syndrome: No difference in incidence or severity until day 7

Vasopressor use, acute kidney injury, RRT

Mean 25-hydroxyvitamin D levels at day 3 higher in the D3 group; 74.5% reached target levels. (measured in a subgroup of the first 25% of patients per protocol); higher (in the 30 to <120 ng/ml range) in treated patients

Safety endpoints:

Prespecified vitamin D– related adverse events: hypercalcemia, kidney stones, and fall-related fractures

The slight increase in the highest total calcium level to day 14 in the vitamin D group. Similarly, there were small increases in total and ionized calcium levels ac-cording to trial day in the vitamin D group

Reported serious and non- serious adverse events were uncommon and similar

Strengths – 

Largest RCT on this topic

Different from previous phase 2

Pragmatic design

Ruled out the role Vit D as a preventative measure

Good internal validity

Weaknesses

Predominately medical patients

Mixed ethnic population

Only ⅓ patients on mechanical ventilation and/or vasopressor support

No data on enteral nutrition

24.8% of still vitamin D level <30ng/ml on day 3

No in patients at a later stage of illness

Author’s Conclusion

A single dose of 540,000 IU vitamin D3 administered early during critical illness rapidly corrected vitamin D; no improvement in clinical endpoints.

Our Conclusion

Very well conducted study.

No place for routine use of Vit D3 in all ICU patients.