Vitamin D and outcomes in adult critically ill patients. A systematic review and meta-analysis of randomized trials

doi:10.1016/j.jcrc.2016.10.029

Journal of Critical Care

Volume 38, April 2017, Pages 109-114

https://doi.org/10.1016/j.jcrc.2016.10.029 Get rights and content

Abstract

Purpose

Low vitamin D blood levels are associated with high mortality in critically ill patients. There is controversy about vitamin D supplementation in this population. The objective of this meta-analysis was to evaluate if vitamin D administration reduces mortality in critically ill patients.

Materials and methods

Online databases were searched up to September 1^st, 2016 for randomized placebo-controlled trials on the use of vitamin D in adult patients with critical illness. The primary end point was mortality among trials with low risk of bias. The secondary end points were length of hospital stay, length of intensive care unit stay, length of mechanical ventilation, and adverse events.

Results

Seven studies published between 2011 and 2016, for a total of 716 patients, were included in the analysis. Vitamin D administration was associated with significantly lower mortality compared with placebo (101/320 [32%] in the vitamin D group vs 123/307 [40%] in the placebo group; odds ratio, 0.70 [95% confidence interval, 0.50 to 0.98]; P = .04; I² = 0%). No differences in adverse events and other secondary end points were found.

Conclusions

In critically ill patients, vitamin D administration might be associated with a reduction in mortality without significant adverse events. A large multicenter randomized trial should conclusively confirm these findings.

Introduction

Millions of patients receive vitamin D supplementation every year [1], [2] and more than one-third of the US adult population takes vitamin D supplements [2]. Beside its involvement in bone metabolism and calcium and phosphorus homeostasis, vitamin D is widely recognized to have other nonskeletal pleiotropic effects, including immunomodulatory, antimicrobial, cardiovascular, and muscular effects [3], [4].

Hypovitaminosis D is common in the general population [1] and increases up to 82% in critically ill patients [5], [6], [7], [8]. Unfortunately, vitamin D deficiency is associated with increased mortality both in the overall population [4], [9] and in critically ill patients [5], [6], [7], [10], [11], [12], [13]. Low vitamin D plasma levels are also associated with an increased susceptibility to sepsis [14] and with an increased mortality in patients with sepsis [5], [11], [12]. Low vitamin D plasma levels were found to be associated with the intensive care unit (ICU) and hospital length of stay in patients undergoing cardiac surgery [15] or with sepsis [5].

Vitamin D is considered biologically inactive until it undergoes 2 enzymatic hydroxylation reactions; the first reaction takes place in the liver forming 25-OH vitamin D and the second takes place in the kidney forming the biologically active hormone, calcitriol (1,25-OH vitamin D) [16]. Vitamin D levels are affected by several factors, such as vitamin D intake, sun exposure, adiposity, age, and skin melanin content in the overall population [4], [17]. Notably, vitamin D levels are worsened by immobilization, kidney disease, fluid overload, and inflammation, conditions which occur frequently in critically ill patients [15], [18], [19].

Millions of patients per year are admitted in the ICU [20], and even more are admitted to an intermediate care unit or an acute medical unit. Despite improvement in technology and patients' care, mortality in critically ill patients remains high. Interventions aimed at reducing mortality are strongly warranted and even a small reduction in mortality can save thousands of patients worldwide. To this aim, there is controversy about vitamin D supplementation in critically ill patients [9], [21], [22]. Several studies have found that vitamin D supplementation might be associated with a reduction in all-cause mortality in various settings, including healthy subjects and cancer patients [23], [24], [25]. The largest randomized controlled trial (RCT) performed so far in critically ill patients was underpowered to detect differences in mortality but found promising effects of vitamin D supplementation in the subgroup of patients with severe vitamin D deficit [22]. Therefore, we performed a systematic review with meta-analysis of randomized literature to test the hypothesis that vitamin D, as compared with placebo, reduces mortality in critically ill patients.

Section snippets

Eligibility criteria

Eligible studies met the following PICOS criteria: (1) population, adult hospitalized critically ill patients; (2) intervention, administration of vitamin D; (3) comparison intervention, placebo-control; (4) outcome, mortality; (5) study design, RCT. There was no restriction on vitamin D formulation and dose or time of administration. The exclusion criteria were overlapping populations and pediatric studies.

Search strategy

Two investigators independently searched BioMedCentral, PubMed, EMBASE, and the Cochrane

Literature search

The search strategy yielded 7262 citations (Fig. 1) and a total of 23 studies were assessed in detail. Major exclusions were due to pediatric setting (n = 5) [30], [31], [32], [33], [34], overlapping populations (n = 5) [35], [36], [37], [38], [39], lack of a randomized design (n = 3) [40], [41], [42], abstract-only publications with lack of mortality data (n = 2) [43], [44], and absence of control group (n = 1) [45]. Finally, 7 articles [22], [46], [47], [48], [49], [50], [51] (716 participants) were

Discussion

The most important findings of our meta-analysis are that vitamin D supplementation might reduce mortality in critically ill patients and that enteral administration is effective in increasing vitamin D blood levels compared with placebo, without major adverse events. No statistically significant differences in length of ICU and hospital stay were found.

The underlying mechanisms by which critically ill patients may benefit from vitamin D supplementation remain to be investigated. Vitamin D

Conclusions

Current randomized evidence suggests that the administration of vitamin D could reduce mortality in critically ill patients. Considering the absence of major adverse effects, the effectiveness in increasing vitamin D blood levels, and the possible effect on survival, vitamin D supplementation is a very attractive intervention for future investigations aimed at reducing mortality in critically ill patients. A multicenter randomized placebo-controlled trial adequately powered for mortality should

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This single-center retrospective study included liver transplant recipients from June to November 2017 who had preoperative 25-OH-vitamin D3 (25-OH-D3) data. Severe vitamin D deficiency, insufficiency, and normal levels were defined as serum 25-OH-D3 concentrations of < 10 ng/mL, 10 to 20 ng/mL, and ≥ 20 ng/mL, respectively. The primary outcome was length of hospital stay; secondary outcomes included the duration of normalization of inflammatory markers after liver transplant, new infection rates, rejection rates, length of intensive care unit stay, and mortality according to preoperative 25-OH-D3 levels.
Among 219 liver transplant recipients, 67.6% were vitamin D-deficient. The mean (standard deviation) 25-OH-D3 concentration was 17.8 (13.2) ng/mL, and 65 (29.7%) patients had levels < 10 ng/mL. Patients with lower mean 25-OH-D3 levels had significantly longer intensive care unit (13.8 [21.9] days vs 5.9 [12.3] days vs 2.7 [4.6] days, P < .001) and hospital (59.0 [66.0] days vs 42.0 [67.4] days vs 27.2 [17.1] days, P = .001) stays. The incidence of new infections was higher in the vitamin D deficiency group. (46.2% vs 28.9% vs 14.1%, P < .001). A higher Nutritional Risk Screening 2002 score (adjusted odds ratio, 1.77; 95% confidence interval [CI], 1.24-2.56; P = .002) and severe vitamin D deficiency (adjusted odds ratio, 3.43; 95% CI, 1.57-7.57; P = .002) were significant risk factors for poor outcome among patients who had been in the hospital for more than 43 days.
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Citation Excerpt :
In some countries, oral calcifediol [25(OH)D] is available and may be a good alternative as it has a higher rate of intestinal absorption, and this may have important advantages in case of decreased intestinal absorption capacity [639]. Three meta-analyses on vitamin D in critical care have been published, each one with important limitations and differing results [640–642]. The VIOLET trial including 1078 adult ICU patients with low vitamin D (25(OH)D < 20 ng/ml [50 nmol/]) did not show a difference between the placebo group and the vitamin D group [643]: a one-time ultra-high loading dose (540,000 IU) was given without a maintenance dose.
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This guideline aims to provide information for daily clinical nutrition practice regarding assessment of MN status, monitoring, and prescription. It proposes a consensus terminology, since many words are used imprecisely, resulting in confusion. This is particularly true for the words “deficiency”, “repletion”, “complement”, and “supplement”.
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^☆: Conflict of interest and funding: The authors declare no potential conflict of interest. The authors have no support or funding to report. The study did not receive any funding.

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Outcomes/PredictionsVitamin D and outcomes in adult critically ill patients. A systematic review and meta-analysis of randomized trials☆

Abstract

Purpose

Materials and methods

Results

Conclusions

Introduction

Section snippets

Eligibility criteria

Search strategy

Literature search

Discussion

Conclusions

Chem Biol

Mayo Clin Proc

Lancet Diabetes Endocrinol

Crit Care

Nutrition

Clin Nutr

Nutrition

J Steroid Biochem Mol Biol

Bone

J Clin Transl Endocrinol

Hum Immunol

Arch Biochem Biophys

Am J Clin Nutr

Vitamin D: increasing supplement use in at-risk groups—guidance and guidelines

Dietary supplement use among U.S. adults has increased since NHANES III (1988-1994)

NCHS Data Brief

Vitamin D status and its association with season, hospital, and sepsis mortality in critical illness

Crit Care

Significant perturbation of vitamin D-parathyroid-calcium axis and adverse clinical outcomes in critically ill patients

Intensive Care Med

Vitamin D deficiency in critically ill patients

N Engl J Med

Is vitamin D insufficiency associated with mortality of critically ill patients?

Crit Care Res Pract

Deficiency in 25-hydroxyvitamin D and 30-day mortality in patients with severe sepsis and septic shock

Am J Crit Care

Serum 1,25-dihydroxyvitamin D: an outcome prognosticator in human sepsis

PLoS One

Vitamin D deficiency is associated with mortality in the medical intensive care unit

Crit Care

Significant association between vitamin D deficiency and sepsis: a systematic review and meta-analysis

BMC Anesthesiol

Institute of Medicine (US) committee to review dietary reference intakes for vitamin D and calcium

Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women

J Inflamm (Lond)

Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients

Crit Care

Variations in serum 25-hydroxyvitamin D during acute pancreatitis: an exploratory longitudinal study

Endocr Res

National growth in intensive care unit admissions from emergency departments in the United States from 2002 to 2009

Acad Emerg Med

Vitamin D supplementation in the ICU patient

Curr Opin Clin Nutr Metab Care

Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial

JAMA

Meta-analysis of long-term vitamin D supplementation on overall mortality

PLoS One

Outcomes/Predictions
Vitamin D and outcomes in adult critically ill patients. A systematic review and meta-analysis of randomized trials☆