Vitamin D status in critical care: Contributor or marker of poor health?

In the last decade, few substances had been investigated and discussed as intensely and controversially as vitamin D. In the last 5 years, vitamin D research has also reached the intensive care unit (ICU). In this issue , Padhi and colleagues[1] report important observational data on the prevalence of vitamin D deficiency and its association with important clinical outcomes of 152 adult patients in eastern India. The study took place over a 6-month period in spring/summer in the medical ICU of a large teaching hospital treating primarily patients from the lower middle class and below poverty line. To my knowledge, this Indian study is the first report in Asia and shows a similarly high percentage (52%) of vitamin D deficiency (<20 ng/ml) in this vulnerable population, compared to previous reports from Europe, North America, and Australia.[2] Unfortunately, currently no uniform definition of vitamin D deficiency is used, although it is clear that 25-hydroxyvitamin D [25(OH) D] represents body vitamin D stores the best.

Surprisingly, despite limited sample size, the authors were able to show significantly worse outcomes in patients with 25(OH) D levels <20 ng/ml compared to patients with normal levels. This was seen for hospital mortality and ICU length of stay. Interestingly, although the percentage of patients requiring invasive mechanical ventilation was similar, the duration was significantly shorter in patients with sufficient vitamin D status. A new finding in this study is that significantly more women had low vitamin D levels. This is plausible taking into account that women in this region often wear clothing that covers the largest part of their skin, thus substantially reducing cutaneous vitamin D synthesis. Moreover, although difficult to assess, malnutrition and preexisting diseases certainly also played a contributing role to the high prevalence of vitamin D deficiency found in this cohort.

One of the most important limitations of the study is that severity of illness was not taken into account for the analyses. When assessing vitamin D status during critical illness, a number of ICU-specific factors like fluid loading and inflammatory status need to be taken into account. Certainly, reverse causality must also be considered, particularly in critically ill patients who often have substantial comorbidities even before critical illness. Vitamin D definitely is a marker of poor health and immobility. In this regard, the most important chronic disease that affects vitamin D status is chronic kidney disease. In a rat model, it has been convincingly shown that uremia leads to lower 25(OH) D levels and lower 25(OH) D response to a given native vitamin D dose (ergocalciferol or cholecalciferol).[3]

Until today, only four small intervention trials, too small to assess clinical outcomes, have been published in adult critical care, and these trials used very different dosing regimens.[4] The first large randomized controlled trial (RCT) has recently been conducted in Austria,[5] but the results are not yet published. Thus, it currently remains unclear if vitamin D status is merely a marker of poor health or if vitamin D itself may improve outcomes in this setting.

How should one single vitamin have such an impact on diverse outcomes and even mortality? There are several reasons. Vitamin D, in reality, is not a “simple” vitamin, but rather fulfills the criteria of a steroid hormone - it acts on the intracellular vitamin D receptor (VDR) that is present in many cell types and regulates transcription of a substantial number of genes.[6] Thus, it is biologically plausible that vitamin D deficiency leads to impaired functionality of the immune, cardiovascular, and musculoskeletal systems, which may well translate into excess morbidity and mortality and prolonged length of stay in an intensive care setting.

So, why is there such a discrepancy in the results of recent large systematic reviews and meta-analyses that failed to clearly show a benefit of vitamin D supplementation in other populations? Because it is impossible to extract valid results if the “raw material” is methodologically flawed, and surprisingly, many vitamin D RCTs did not follow basic rules:[7] many included patients regardless of their baseline status (so, many did not have vitamin D deficiency), many did not assess the vitamin D status before and/or after the intervention (thus, the used dose may have been too small), and many trials were simply underpowered.

Although the effectiveness of vitamin D non-skeletal outcomes continues to be debated, it is generally agreed upon that a 25(OH) D level of >20 ng/ml is desirable, at least for optimal bone health.[8] So, what should be done with the presented data? Native vitamin D is ridiculously inexpensive in comparison to other drugs and interventions used in critical illness. Moreover, vitamin D has the (yet unproven) potential to improve outcomes in critical illness, as opposed to a very low risk of adverse effects. On the other hand, 25(OH) D testing is relatively expensive. Thus, when resources are limited, it seems reasonable to generally apply the available 2011 Endocrine Society Guidelines for patients at risk of vitamin D deficiency, which recommend 1500-2000 IU of daily oral cholecalciferol or ergocalciferol[9](which is certainly justified if more than half of the studied population is affected as demonstrated in the current study). In most ICU patients, however, these doses will unlikely be able to substantially improve vitamin D status during critical illness. A dose of 10,000 IU daily is reported to be safe[9] and may work better. Loading doses followed by regular maintenance doses guided by 25(OH) D levels may be another option.

Until data from large intervention trials required to assess the true benefits and optimal treatment regimens of vitamin D in this special setting are available, the high prevalence of vitamin D deficiency found in critical illness worldwide should prompt us to supplement vitamin D at least during critical illness and recovery, as suggested by current guidelines. When ICU stay may be anticipated as before elective major surgery, restoration of vitamin D stores before the event is certainly even better.