01 Oct Effect of High-Dose Vitamin D Supplementation In Critically Ill Patients
Medical Research: What are the main findings of the study?
Dr. Amrein: This is the first large clinical trial on vitamin D in critical care. In a double-blind, randomized, placebo-controlled clinical trial, a population of mixed adult ICU patients with vitamin D deficiency (defined as 25-hydroxyvitamin D [25(OH)D] level ≤ 20ng/ml) was assigned to receive either vitamin D3 or placebo. We used a high loading dose of vitamin D3 followed by monthly maintenance doses of 90,000 IU for a total of 5 months. Because of a substantially increased risk for skeletal complications below 12ng/ml of 25-hydroxyvitamin D, we used this threshold for a predefined subgroup analysis.
Overall, high-dose vitamin D3 compared with placebo did not reduce hospital length of stay (primary endpoint), intensive care unit (ICU) length of stay, hospital mortality, or 6 month-mortality
Medical Research: What was most surprising about the results?
Dr. Amrein: In the predefined subgroup with severe vitamin D deficiency (≤12ng/ml, n=200 or 42% of the total population), hospital and ICU length of stay were also not different, but hospital mortality was substantially and significantly lower in the vitamin D compared to the placebo group (relative reduction of 44%, absolute reduction of 17.5%). Originally, we had chosen hospital length of stay as a primary endpoint because we were unable to imagine that the mortality benefit could be so large.
We are, however, unable to answer the question why the mortality was reduced in the subgroup with severe vitamin D deficiency – there was a reduction in the causes of death for every category. It has to be acknowledged that our study was a pragmatic single-center study that was unable to assess all variables that we would have liked to.
The subgroup with less severe vitamin D deficiency did not have a difference in survival, but there seem to be benefits for several morbidity outcomes.
What was also surprising was that only about half of the patients were able to reach normal vitamin D levels with this large loading dose. This may be attributable to severe gastrointestinal dysfunction during critical illness and also in part to low vitamin D binding protein levels in an acute inflammatory state. We chose our regimen of monthly doses because it is easy to control. As vitamin D normally has a half-life of 2-3 weeks, it may be more physiological to give smaller, more frequent doses.
Medical Research: What should clinicians and patients take away from your report?
Dr. Amrein: I believe our study justifies vitamin D screening in truly critically ill patients (not those who only stay overnight). Currently, a very low dose (200 IU daily) of vitamin D is recommended for patients who receive nutrition. This is certainly inadequate.
Although there is some controversy on the validity of vitamin D levels in acute illness, at least when 25(OH)D levels are below 12ng/ml, vitamin D3 supplementation should be considered according to current guidelines (Endocrine Society 1500-2000 IU daily, upper limit 10,000) during critical care.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Amrein: What we need now is a larger, much better funded, multicenter trial including critically ill children and adults with vitamin D deficiency, ideally with several treatment regimens, including a high doses intravenous formulation (that is currently not commercially available). Also, infectious and musculoskeletal outcomes should be better assessed than we were able to as vitamin D plays a crucial role in these organ systems.
If our results are confirmed and extended, this would be a truly spectacular innovation in intensive care because vitamin D is ridiculously cheap, has a very good benefit – risk profile and is available worldwide. Moreover, there are few interventions that have ever substantially decreased the mortality risk in this extremely vulnerable population – early goal directed therapy in sepsis or prone positioning in acute respiratory distress syndrome would be examples.