Thank you for joining me to discuss the implications of vitamin D in critical illness, which I have playfully subtitled, Sunshine vs. Badness. My name is Jeremiah Duby. In my day job, I am an embedded member of the Surgical Critical Care team at the University of California, Davis Medical Center. I also teach at Terry University College of Pharmacy and a precepts student for the University of California, San Francisco. The image on the left is of Playa Tamarindo in Calabria, Puerto Rico, which I took while attending the 42nd Critical Care Congress in 2013. Here again are my academic and professional affiliations. I have no conflicts of interest to report. In this presentation, we will characterize the effects of vitamin D deficiency in critically ill patients, review the available clinical trials, and explore elements of vitamin D replacement such as population, dosing, safety, and monitoring. In brief, we will examine why vitamin D deficiency is important in critical illness, what we can imply in terms of evidence-based medicine, and the who and how to provide vitamin D replacement. In brainstorming this topic, it readily became clear that our understanding of the basic physiology of vitamin D deficiency is relatively limited. For example, we do not know what levels of deficiency affect the course of critical illness broadly, or in specific populations, or in the setting of other hormone deficiencies. Further, research appears to be in the early stages of exploring these questions in the clinical setting, therefore there is little in the way of clear guidance for bedside application. However, answers are starting to emerge to the practical questions, such as agent, dose, frequency, and monitoring. As always, it is useful to start with what we do know. We know that exposure to sunlight is essential to synthesizing adequate levels of vitamin D. We also know that the Earth is not the center of the solar system, and that planetary orbits are not perfectly round. Beyond photochemical synthesis, the list of dietary sources of vitamin D is relatively narrow. Normal sources include fatty fish, such as salmonoids and mackerel, beef liver, egg yolk, and dairy products which are fortified with the supplement. Strikingly, mushrooms are the only common plant-based source of vitamin D. We also know that vitamin D is not really a vitamin at all, but rather a pro-hormone. Moreover, vitamin D manifests as a multitude of active metabolites, which likely explains a wide range of physiologic effects. Finally, variable rates of conversion from vitamin D2 and D3 to more potent metabolites may explain some of the observed differences in clinical outcomes. The significance of vitamin D was discovered through the skeletal disorders that result from severe chronic deficiency of vitamin D, such as Ricketts disease. We know that calcium is essential to bone growth and metabolism, and that vitamin D regulates calcium resorption and mobilization to maintain adequate calcium levels in the blood. Vitamin D and other fat-soluble vitamins A, E, and K are transported in chylomicrons and absorbed via lacteals, which are specialized lymphatic vessels in the small intestine. Vitamin D is vital to the expression of hundreds of genes throughout the body. In its immunomodulatory role, vitamin D promotes cell differentiation and synthesis of antimicrobial peptides, it purportedly has anti-inflammatory properties, and it facilitates membrane stabilization in the gut and lung. Vitamin D is also critical for skin growth and repair, which may be especially important for populations such as burn and surgery patients. Shifting now to the clinical setting, what are the implications of vitamin D deficiency in critical illness? The high prevalence of vitamin D deficiency may be readily explained in the context of the manifold causes. First, there is a substantial gap between the recommended daily intake of 600 to 800 international units per day versus the average dietary intake of less than 300. In the ICU setting, this baseline deficiency is compounded by a deficiency of sunshine, decreased dietary intake, and altered absorption from the small bowel. Conversion of vitamin D2 or vitamin D3 may be further hindered by decreased hepatic and renal conversion to potent metabolites. Finally, conditional deficiencies may arise when tissue demand exceeds supply. As we examine the literature, we will be confronted with the question of whether vitamin D deficiency is a cause or simply a signal associated with poor clinical outcomes. In the general population, vitamin D deficiency is associated with elderly age, diminished micronutrient intake, increased BMI, decreased physical activity, comorbidity, and, of course, a deficiency of sunshine. Interest in vitamin D in critical illness has increased substantially in the last 5 to 10 years. One of the first studies to investigate the relationship between vitamin D and clinical outcomes was performed in critically ill surgical patients. The objectives of the prospective observational study were to characterize vitamin D status at initiation of critical care in surgical patients and to determine whether vitamin D status is associated with the risk of prolonged hospital length of stay, 90-day readmission, and 90-day mortality. The study investigators chose a 25-hydroxyvitamin-D level of 20 nanograms per ml as a breakpoint of comparison. Perhaps the most striking baseline characteristic was a high prevalence of vitamin D deficiency. 63% of surgical patients enrolled in the study exhibited a significant deficiency at the start of their critical illness. Vitamin D levels for patients in the cohort with deficiency were approximately half that of the comparator group. It's worth noting that levels in the comparator were consistent with vitamin D insufficiency, which is defined as a level of 20 to 30 nanograms per ml. Vitamin D deficiency was associated with an increase in hospital length of stay, 90-day ICU readmission, and 90-day mortality. This next study also endeavored to explore the effects of vitamin D deficiency on the course of critical illness. The purpose of this retrospective observational study was to evaluate the prevalence of vitamin D deficiency and the correlation between vitamin D levels and hospital and sepsis mortality in adult surgical and medical ICU patients. Deficiency was defined as a level less than 20, insufficiency as a level of 20 to 30, and normal levels as those above 30 nanograms per ml. Again, the most notable baseline characteristics were the relatively high rates of deficiency and insufficiency. This graphic illustrates the relative proportion of each group. As you can see, over 60% of patients had baseline vitamin D levels consistent with deficiency. Moreover, only 1 in 7 patients had adequate levels at baseline. There was no difference observed in the ICU mortality rate between the groups. However, hospital mortality, sepsis mortality, and ICU length of stay were consistently highest in the cohort of patients with a deficiency. Finally, a recent secondary analysis of the alveoli study examined the relationship between vitamin D levels and outcomes in patients with ARDS. The study objective was to investigate whether baseline vitamin D status is associated with important clinical outcomes in adult patients with ARDS. Patients were divided into three cohorts based on vitamin D levels at study enrollment. The primary outcome was 90-day survival. As you can see from the histogram, 40% of patients met the criteria for severe vitamin D deficiency, 90% of patients had levels less than 20 nanograms per ml, and only 4% of patients had levels in the normal range. Remarkably, only about 10% of patients had levels above 20 nanograms per ml, but the groups were remarkably similar in their other baseline characteristics. As you can see at the bottom of the table, there was a substantial and statistically significant difference in 28-day ventilator-free days favoring patients in the cohort with higher vitamin D levels. This advantage extended to 90-day survival such that patients with severe vitamin D deficiency depicted by the blue line experienced a significantly higher rate of mortality. The link between vitamin D and COVID-19 was explored in a number of trials, which we will review in this meta-analysis published in 2021. The combined number of subjects is relatively small, however these findings suggest a trend towards a survival benefit in patients with vitamin D levels above 20 nanograms per ml. Here again, there was likely an inadequate number of subjects to explore the effects of vitamin D deficiency on ICU admission and mechanical ventilation. The trend towards an increased risk of contracting COVID-19 also failed to achieve statistical significance despite a much larger combined cohort. In summary, vitamin D deficiency is very common in critically ill patients and it is associated with an increased length of stay and mortality. Next, let us explore the clinical trials of vitamin D replacement. Before we start, it is worth considering some of the challenges facing the investigators. First, we are confronted with the prospect of correcting a chronic deficiency in the acute care setting. Then, there is the humbling recognition that we do not know what agent, dose, frequency, or duration to apply. We do not even know the optimal levels for the critically ill population or subpopulations. We cannot even say with certainty what we expect in terms of cellular targets, effects, or timeline. Vital ICU represented one of the first prospective randomized controlled trials to investigate the effects of vitamin D on clinical outcomes in critically ill patients. The objective of this study was to investigate whether a vitamin D3 regimen is of health benefit for patients in the ICU. Adults, surgical, and medical patients with vitamin D deficiency, defined as a level less than 20 nanograms per ml, were included. Vitamin D3 was entirely administered as a bolus dose of 540,000 international units followed by 90,000 international units every month for five doses. The primary outcome was hospital length of stay. There was no difference in mortality between the placebo and vitamin D3 groups overall. However, patients in the pre-specified subgroup of severe vitamin D deficiency appeared to experience a lower rate of mortality at 28 days during hospitalization and at six months. Again, the difference in survival and the intention to treat group failed to achieve statistical significance. However, there appeared to be a substantial and sustained difference in mortality favoring patients with severe vitamin D deficiency who received high dose vitamin D3. The VIOLET study investigated the effect of early, high dose vitamin D3 on critically ill patients with vitamin D deficiency. VIOLET was a randomized, double-blind, placebo-controlled phase 3 trial in adult patients admitted to the ICU with vitamin D deficiency and at least one risk factor for death or lung injury. Patients in the intervention group were given a single 540,000 international unit bolus dose of vitamin D3. The primary outcome was 90-day all-cause mortality. Unfortunately, the study was stopped after the first interim analysis due to futility based on the estimated effect size. Finally, let's take a quick look at a recent meta-analysis exploring the effects of vitamin D replacement. The first thing you notice about the studies in critically ill patients is extreme heterogeneity in terms of population, intervention, and outcome. The other striking thing is that most interventions applied very large bolus doses. There was no difference observed in 28-day mortality. No differences were observed in ICU or hospital length of stay. However, there was a statistically significant difference in the duration of mechanical ventilation favoring the patients that received vitamin D. In summary, there appears to be a mortality benefit for vitamin D3 replacement in patients with severe deficiency, defined as a level less than 12 ng per ml. There also appears to be an advantage to vitamin D replacement in duration of mechanical ventilation. However, these benefits were not observed in patients with less severe deficiency. And it is worth noting that vitamin D replacement was well tolerated. Finally, no clear strategy for dosing, duration, or monitoring has yet emerged. The majority of clinical trials employed large loading doses. However, this strategy is no longer recommended on the basis that it induces 24-hydroxylase, which catalyzes vitamin D for up to 28 days after exposure. Further studies may employ active metabolites directly to bypass the variable rates of conversion that occur with hepatic and renal impairment. Patient selection is also likely to target patients with severe deficiency as they appear to experience the greatest benefit from treatment. So, who should we consider for vitamin D replacement, and how should we deliver this therapy? Patients with severe vitamin D deficiency appear to benefit the most from replacement. You may also consider patients with ARDS and patients at risk for COVID infection and or complication. In general, vitamin D replacement is well tolerated and inexpensive. There is no consensus or clear guidance on agent or dose, but vitamin D3 was used in most clinical trials. A moderate bolus dose may be reasonable, but a maintenance dose is likely necessary to maintain adequate levels of active metabolites. Vitamin D replacement is extremely well tolerated, even at doses 5-10 times the recommended daily allowance for prolonged periods of time. Types of toxicity include hypercalcemia, weakness, dry mouth, and nausea. 25-hydroxyvitamin D is the most common biomarker employed and appears to track well with other forms of vitamin D in clinical trials. There is no clear guidance on the frequency of monitoring. However, logical reasoning suggests more frequent monitoring for higher doses of replacement or supplementation. Thank you for your time and attention.

vitamin D deficiency

critically ill patients

mortality

clinical trials

vitamin D replacement