Vitamin D loading doses typically helped critically ill, but never harmed (21 RCTs) - Jan 2025

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Evaluation of Vitamin D Supplementation in Critically ill Patients - A Systematic Review of the Last 5 Years

Preprints.org doi:10.20944/preprints202501.1623.v1
Shan Wang 1, Ruodi Ren 2, Kunkun Wang 3, Christopher Leo 4, Mengyan Li 5, Allison Chow 6, Andrew Yang 7 and Yun Lu 8,*
NYU Langone Hospital - Long Island, Mineola, NY 11501
University of Minnesota, MN, 55415
Fairbanks Memorial Hospital, 340 Cowles Street, Fairbanks, AK 99701
Duke Raleigh Hospital, a campus of Duke University Hospital, School of Medicine, Duke University, Durham, NC, 27708
Brigham and Women's Hospital, Boston, MA 02115
New York University, New York, NY 10012
University of Minnesota, Minneapolis, MN
College of Pharmacy University of Minnesota, Hennepin Healthcare System, Minneapolis, MN 55415 yun.lu at hcmed.org

Vitamin D deficiency was found to be associated with increased risks of infection, morbidity, and mortality in critically ill patients. However, current critical care guidelines do not recommend routine vitamin D supplementation. We conducted a literature search using Medline, Embase, Web of Science and Cochrane databases for randomized controlled trials published in the past five years on vitamin D supplementation in ICU patients. We analyzed data from 21 studies, reviewing dosing strategies, administration routes, baseline vitamin D levels, and clinical outcomes such as biomarker changes, mechanical ventilation duration, hospital length of stay, and mortality. Our results suggest that vitamin D supplementation may be safe and potentially beneficial in reducing ICU length of stay and time on mechanical ventilation. However, the impact on overall mortality remains uncertain. Our findings emphasize the need for individualized clinical decision­making regarding vitamin D supplementation in critically ill patients, considering baseline vitamin D levels, patient characteristics, severity of illness, and administration methods.
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Discussion

Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial conducted by The National Heart, Lung, and Blood Institute PETAL clinical trial group (2019) showed early administration of a single high-dose 540,000 IU of vitamin D3 enterally in critical-ill patients with vitamin D deficiency ( (25-hydroxyvitamin D level, <20 ng/ml) increases vitamin D serum level but did not demonstrate any clinical benefit over placebo in 90-day mortality or other nonfatal outcomes [8]. This group conducted an ancillary study, VIOLET Long-term Brain Outcomes in Vitamin D Deficient Patients (VIOLET-BUD) [17] . This study evaluated the same single enteral high dose of vitamin D vs placebo in vitamin D deficiency patients on their long-term cognitive outcomes at a median of 443 days (interquartile range, 390-482 days). Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [25] was evaluated for long term cognitive outcomes and executive function (composite score derived from three Delis-Kaplan Executive Function System Subscales [26]). It concluded that a single high dose of enteral vitamin D did not improve long-term global cognition or executive function in critically ill patients with vitamin D deficiency.
Overall, conflicting results were demonstrated in the randomized controlled trials in the past 5 years regarding the clinical impact of vitamin D replacement on critically ill patients. Several studies showed vitamin D replacement has positive results in biomarkers such as procalcitonin, Cathelicidin LL-37, neutrophil-to-lymphocyte ratio(NLR) and platelet-to-lymphocyte ratio (PLR) levels [27]. Other studies demonstrated that vitamin D improved SOFA score, GCS score, post-op infection rate, duration of mechanical ventilation, and ICU and hospital length of stay [24].
On the contrary, studies also demonstrated no differences between the vitamin D replacement group and placebo group in regards to ICU and hospital LOS and duration of mechanical ventilation. In one of the biggest studies, with a cohort of 1078 patients, early administration of high-dose enteral vitamin D3 540,000 IU did not improve 90-day mortality and other clinical outcomes of vitamin D-deficient patients [8].
It was demonstrated that the vitamin D supplementation in ICU patients with low baseline vitamin D levels does not increase the serum 25-(OH)-D levels as much as expected [20]. This may be due to an increased distribution volume or an accelerated breakdown [20]. Additionally, vitamin D supplementation increased the serum level of 25-(OH)-D but there was no rise in 1, 25 (OH)2D, suggesting that 25-(OH)-D is not metabolized to the active hormone 1, 25 (OH)2D. It is speculated that CYP27B1 (also known as 1-alpha hydroxylase) is downregulated during critical illness, which compromises the conversion of 25OHD to 1, 25(OH)2D, and possibly shifts the metabolization of 25OHD to other compounds. Small rise in 24, 25 (OH)2D was also noticed, which might serve as a feedback mechanism of avoiding vitamin D toxicity. These findings could be part of an adaptive response to critical illness [20]. On the other hand, the vitamin D supplementation dose in the study of Ingels et al. is very low (loading dose of 8,000 IU and daily maintenance of 600 IU x10 days), compared to vitamin D doses in other studies. This could be the reason why Ingels et al did not find any significant benefit of vitamin D replacement in ICU patients.
The strategies to replace vitamin D also vary across studies. The dose and route of vitamin D replacement remains institutional and protocol-specific. In studies that show vitamin D replacement with positive clinical impacts, the vitamin D dose ranges from 5,000 IU to 540,000 IU as a single dose or multiple-day replacement. The vitamin D was given either via enteral or intramuscular route. In several studies, vitamin D was supplemented in patients who were found to have vitamin D deficiency; in other studies, the critically ill patients were supplemented with high dose vitamin D without knowing their baseline vitamin D level. The optimal timing of vitamin D replacement upon intubation is also unclear. Fortunately, no toxicity from vitamin D supplementation was reported in patients among all studies reviewed.
The promising role of vitamin D in patients with severe vitamin D deficiency has been identified and confirmed in several studies [5,7,10,12,13,18,19,22]. Even though in VITdAL-ICU, the use of vitamin D3 supplement did not show beneficial effects on duration of hospital stay or ICU stay as well as hospital mortality and 90-day mortality, one of the post-hoc study of VITDAL-ICU focused on the subgroup analysis on patients with severe vitamin D deficiency (defined as vitamin D level < 12ng/ml) identified a significant reduction in 28-day mortality with the use of vitamin D3 supplements (HR 0.52, [0.30-0.89]) [28]. Bhattacharyya et al performed a subgroup analysis in regards to clinical effects of vitamin D3 supplements on patients with severe vitamin D deficiency (vitamin D levels <12 ng/mL) [4]. The results showed that vitamin D replacement significantly decreased the use of mechanical ventilation, as well as a trend in reducing 90-day mortality (HR 0.449, [0.198­1.017]). An ongoing trial VITDALIZE trial has specifically focused on the critically ill patients with severe vitamin D deficiency [29]. This study is designed to enroll 2400 patients with a primary endpoint of 28-day mortality. The outcome of this trial is expected to be reported in 2026, which may provide us with more robust evidence on vitamin D replacement in patients with severe vitamin D deficiency.
Of all trials included, Thampi et al, Sistanzid et al, and Naguib et al used synthetic vitamin D analogs as a vitamin D replacement form [3,6,18]. Thamp et al and Sistanzid et al used calcitriol in the sepsis population and no significant results were identified [3,6]. Naguib et al used alfacalcidol orally for patients scheduled for elective mechanical valve replacement surgery [18]. Although no significant difference in hospital mortality was identified, there was a significant reduction in ICU length of stay and postoperative infection rate. Generally, vitamin D analogs were not suitable for vitamin D replacement due to its narrow therapeutic range, lack of feedback control resulting in increased risk for hypercalcemia [30]. It is indicated for hypocalcemia, osteoporosis, and the prevention of corticosteroid-induced osteoporosis [31]. Given the high incidence of acute kidney injury in acute illness and high level of monitoring in ICU, it is arguable that active or partially active vitamin D analogs are more suitable for the critically ill population. Further studies should be designed to evaluate their efficacy and safety in this context.
Masbough et al. and Sharma et al. both investigated vitamin D in traumatic brain injury patients [7,13]. Surprisingly, both studies found a statistically increase in GCS scores. Sharma et al. reported improvement in biomarkers and shorter mechanical ventilation days. Similarly, Hansaloei et al. reported significant reduction in biomarkers, SOFAscore, duration of mechanical ventilation days and length of ICU stay in traumatic injury patients admitted to ICU [20]. The effect of preoperative vitamin D replacement was investigated by Hajimohammadebrahim-Ketabforoush et al and Naguib et al. for craniotomy for brain tumor resection and elective mechanical valve replacement surgery, respectively, both reported statistically significant reduction in ICU length of stay [18,19]. Low vitamin D level was associated with adverse outcomes with various surgical procedures [32]. With a relatively low patient population enrolled in these trials, the positive findings regarding GCS scores and reduced ICU length of stay suggest that this area could benefit from further exploration with larger patient enrollment to confirm these results and potentially identify a reduction in other outcomes in surgical patients.
Vitamin D deficiency in ICU patients is attributed to both pre-existing insufficiency and a decline in levels during acute illnesses [33,34]. Mechanisms contributing to reduced vitamin D levels during acute illness may include hemodilution, interstitial extravasation, decreased synthesis of binding proteins, and renal loss [35]. In addition, acute fluid resuscitation in ICU can significantly lower vitamin D level, which may take up to 24 hours to resolve [36]. Thus, interpretations of vitamin D level in acute illness should be performed with caution.
Absorption of vitamin D supplementation can vary in different patient populations. For example, higher BMI is linked to a smaller increase in serum 25(OH)D concentrations. Calcium intake and type of vitamin D (D2- ergocalciferol or D3-cholecalciferol) can affect the dose response of 25 (OH)D to vitamin D. Following oral intake, vitamin D is rapidly absorbed to reach a maximum level at around 24 hours. Levels of 25 (OH)D increase gradually to peak at 7-14 days depending on the dose. For studies that used only single dose vitamin D supplementation, it is questionable how the 25(OH)D concentrations played out. Patients with malabsorption issues such as gastrectomy or bariatric patients might need higher doses of vitamin D compared to others [37]. Lastly, baseline vitamin D levels reflect coexisting conditions, especially in critically ill patients, which could cause residual confounding effects when analyzing results [8].
The impact in clinical outcomes in vitamin D replacement in critically ill patients remains uncertain. High doses of vitamin D up to 540,000 IU have been used in studies to explore impact on duration of mechanical ventilation and length of stay. Given the wide therapeutic index of vitamin D, clinicians may feel comfortable with high dose vitamin D replacement even in absence of baseline vitamin D level. Vitamin D toxicity may occur when serum levels of 25(OH)D concentration are greater than 150 ng/mL, accompanied by normal or elevated values of 1,25(OH)2D concentration. The most common cause of vitamin D toxicity is excessive vitamin D supplementation without frequent monitoring of vitamin D levels. While most cases of vitamin D toxicity do not lead to serious complications or sequelae, it may cause hypercalcemia and acute renal failure, which are important considerations in critical care settings. If a high-dose vitamin D replacement is given, it is reasonable to consider monitoring vitamin D levels together with electrolytes and kidney functions. More studies need to be performed to determine the optimal dosing strategies to replace vitamin D in critically ill patients.

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Conclusions

Vitamin D supplementation is safe to be used in critically ill patients, even when their baseline vitamin D level is not known, because of rare incidence of vitamin D toxicity. The majority of clinical trials showed clinical benefits of vitamin D supplementation in ICU patients in shorter ICU or hospital length of stay, improvement of SOFA score, decrease in duration of mechanical ventilation or 28-day mortality. Therefore, Vitamin D supplementation deserves being considered in the ICU setting, especially with closely monitored vitamin D level.

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Note: Nano-emulsion Vitamin D would far better for ICU

1. Does not require the gut, lymphatic system liver, or kidney to be healthy
2. Gets into the body in hours instead of a week to due not being delayed by any of the above
3. Can be applied topically for those who cannot swish it in their mouth or have poor gut function

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VitaminDWiki - 39 studies in both categories Trauma/Surgery and Loading Dose

This list is automatically updated

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VitaminDWiki – Loading Dose of Vitamin D category contains

209 items in category
see also Overview Loading of vitamin D   Overview Toxicity of vitamin D
Better than Daily 1: Fewer chances to forget, 2) Gets past receptor barrier
Injection category has 68 items
 
It appears that over 1 million Vitamin D loading doses have been taken
Doses ranged from 100,000 to 600,000 IU over a period of a day to a month
No reports of serious adverse reactions
Many studies report on the benefits resulting from loading doses

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