A phase II dose evaluation pilot feasibility randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study).

BACKGROUND: Vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (ICU) and associated with worse clinical course. Trials in adult ICU demonstrate rapid restoration of vitamin D status using an enteral loading dose is safe and may improve outcomes. There have been no published trials of rapid normalization of VDD in the pediatric ICU. METHODS: We conducted a multicenter placebo-controlled phase II pilot feasibility randomized clinical trial from 2016 to 2017. We randomized 67 critically ill children with VDD from ICUs in Canada, Chile and Austria using a 2:1 randomization ratio to receive a loading dose of enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or placebo. Participants, care givers, and outcomes assessors were blinded. The primary objective was to determine whether the loading dose normalized vitamin D status (25(OH)D > 75 nmol/L). Secondary objectives were to evaluate for adverse events and assess the feasibility of a phase III trial. RESULTS: Of 67 randomized participants, one was withdrawn and seven received more than one dose of cholecalciferol before the protocol was amended to a single loading dose, leaving 59 participants in the primary analyses (40 treatment, 19 placebo). Thirty-one/38 (81.6%) participants in the treatment arm achieved a plasma 25(OH)D concentration > 75 nmol/L versus 1/18 (5.6%) the placebo arm. The mean 25(OH)D concentration in the treatment arm was 125.9 nmol/L (SD 63.4). There was no evidence of vitamin D toxicity and no major drug or safety protocol violations. The accrual rate was 3.4 patients/month, supporting feasibility of a larger trial. A day 7 blood sample was collected for 84% of patients. A survey administered to 40 participating families showed that health-related quality of life (HRQL) was the most important outcome for families for the main trial (30, 75%). CONCLUSIONS: A single 10,000 IU/kg dose can rapidly and safely normalize plasma 25(OH)D concentrations in critically ill children with VDD, but with significant variability in 25(OH)D concentrations. We established that a phase III multicentre trial is feasible. Using an outcome collected after hospital discharge (HRQL) will require strategies to minimize loss-to-follow-up. CLINICALTRIALS: gov NCT02452762 Registered 25/05/2015.

Raised FGF23 Correlates to Increased Mortality in Critical Illness, Independent of Vitamin D.

BACKGROUND: Fibroblast Growth Factor (FGF23) is an endocrine hormone classically associated with the homeostasis of vitamin D, phosphate, and calcium. Elevated serum FGF23 is a known independent risk factor for mortality in chronic kidney disease (CKD) patients. We aimed to determine if there was a similar relationship between FGF23 levels and mortality in critically ill patients. METHODS: Plasma FGF23 levels were measured by ELISA in two separate cohorts of patients receiving vitamin D supplementation: critical illness patients (VITdAL-ICU trial, n = 475) and elective oesophagectomy patients (VINDALOO trial, n = 76). Mortality data were recorded at 30 and 180 days or at two years, respectively. FGF23 levels in a healthy control cohort were also measured (n = 27). RESULTS: Elevated FGF23 (quartile 4 vs. quartiles 1-3) was associated with increased short-term (30 and 180 day) mortality in critical illness patients (p < 0.001) and long-term (two-year) mortality in oesophagectomy patients (p = 0.0149). Patients who died had significantly higher FGF23 levels than those who survived: In the critical illness cohort, those who died had 1194.6 pg/mL (range 0-14,000), while those who survived had 120.4 pg/mL (range = 15-14,000) (p = 0.0462). In the oesophagectomy cohort, those who died had 1304 pg/mL (range = 154-77,800), while those who survived had 644 pg/mL (range = 179-54,894) (p < 0.001). This was found to be independent of vitamin D or CKD status (critical illness p = 0.3507; oesophagectomy p = 0.3800). FGF23 levels in healthy controls were similar to those seen in oesophagectomy patients (p = 0.4802). CONCLUSIONS: Elevated baseline serum FGF23 is correlated with increased mortality in both the post-oesophagectomy cohort and the cohort of patients with critical illness requiring intensive care admission. This was independent of vitamin D status, supplementation, or CKD status, which suggests the presence of vitamin D-independent mechanisms of FGF23 action during the acute and convalescent stages of critical illness, warranting further investigation.

[Vitamin C and D supplementation in critically ill patients]. / Supplementierung von Vitamin C und D bei kritisch Kranken.

Micronutrient supplementation as part of the medical nutrition therapy for critically ill patients has received much attention in the past few years. Nevertheless, in clinical practice uncertainty remains about the optimal supplementation strategy, including which substance at which dosage should be administered at what time to specific groups of patients. Thus, the aim of this narrative review is to summarize the current evidence and recommendations for the micronutrients vitamin C and vitamin D. The physiological and pathophysiological roles of both vitamins are presented, recently published clinical trials are discussed, and the recommendations of the current guidelines are summarized. In addition, pragmatic tips for use in everyday clinical practice in the intensive care unit are given.

[Diagnosis and treatment of osteoporosis in patients with chronic kidney disease : Joint guidelines of the Austrian Society for Bone and Mineral Research (ÖGKM), the Austrian Society of Physical and Rehabilitation Medicine (ÖGPMR) and the Austrian Society of Nephrology (ÖGN)]. / Diagnose und Therapie der Osteoporose bei Patienten mit chronischer Niereninsuffizienz : Gemeinsame Leitlinie der Österreichischen Gesellschaft für Knochen- und Mineralstoffwechsel (ÖGKM), der Österreichischen Gesellschaft für Physikalische Medizin und Rehabilitation (ÖGPMR) und der Österreichischen Gesellschaft für Nephrologie (ÖGN).

DEFINITION AND EPIDEMIOLOGY: Chronic kidney disease (CKD): abnormalities of kidney structure or function, present for over 3 months. Staging of CKD is based on GFR and albuminuria (not graded). Osteoporosis: compromised bone strength (low bone mass, disturbance of microarchitecture) predisposing to fracture. By definition, osteoporosis is diagnosed if the bone mineral density T­score is ≤ -2.5. Furthermore, osteoporosis is diagnosed if a low-trauma (inadequate trauma) fracture occurs, irrespective of the measured T­score (not graded). The prevalence of osteoporosis, osteoporotic fractures and CKD is increasing worldwide (not graded). PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT OF CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER (CKD-MBD): Definition of CKD-MBD: a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; renal osteodystrophy; vascular calcification (not graded). Increased, normal or decreased bone turnover can be found in renal osteodystrophy (not graded). Depending on CKD stage, routine monitoring of calcium, phosphorus, alkaline phosphatase, PTH and 25-OH-vitamin D is recommended (2C). Recommendations for treatment of CKD-MBD: Avoid hypercalcemia (1C). In cases of hyperphosphatemia, lower phosphorus towards normal range (2C). Keep PTH within or slightly above normal range (2D). Vitamin D deficiency should be avoided and treated when diagnosed (1C). DIAGNOSIS AND RISK STRATIFICATION OF OSTEOPOROSIS IN CKD: Densitometry (using dual X­ray absorptiometry, DXA): low T­score correlates with increased fracture risk across all stages of CKD (not graded). A decrease of the T­score by 1 unit approximately doubles the risk for osteoporotic fracture (not graded). A T-score ≥ -2.5 does not exclude osteoporosis (not graded). Bone mineral density of the lumbar spine measured by DXA can be increased and therefore should not be used for the diagnosis or monitoring of osteoporosis in the presence of aortic calcification, osteophytes or vertebral fracture (not graded). FRAX can be used to aid fracture risk estimation in all stages of CKD (1C). Bone turnover markers can be measured in individual cases to monitor treatment (2D). Bone biopsy may be considered in individual cases, especially in patients with CKD G5 (eGFR < 15 ml/min/1.73 m2) or CKD 5D (dialysis). SPECIFIC TREATMENT OF OSTEOPOROSIS IN PATIENTS WITH CKD: Hypocalcemia should be treated and serum calcium normalized before initiating osteoporosis therapy (1C). CKD G1-G2 (eGFR ≥ 60 ml/min/1.73 m2): treat osteoporosis as recommended for the general population (1A). CKD G3-G5D (eGFR < 60 ml/min/1.73 m2 to dialysis): treat CKD-MBD first before initiating osteoporosis treatment (2C). CKD G3 (eGFR 30-59 ml/min/1.73 m2) with PTH within normal limits and osteoporotic fracture and/or high fracture risk according to FRAX: treat osteoporosis as recommended for the general population (2B). CKD G4-5 (eGFR < 30 ml/min/1.73 m2) with osteoporotic fracture (secondary prevention): Individualized treatment of osteoporosis is recommended (2C). CKD G4-5 (eGFR < 30 ml/min/1.73 m2) and high fracture risk (e.g. FRAX score > 20% for a major osteoporotic fracture or > 5% for hip fracture) but without prevalent osteoporotic fracture (primary prevention): treatment of osteoporosis may be considered and initiated individually (2D). CKD G4-5D (eGFR < 30 ml/min/1.73 m2 to dialysis): Calcium should be measured 1-2 weeks after initiation of antiresorptive therapy (1C). PHYSICAL MEDICINE AND REHABILITATION: Resistance training prioritizing major muscle groups thrice weekly (1B). Aerobic exercise training for 40 min four times per week (1B). Coordination and balance exercises thrice weekly (1B). Flexibility exercise 3-7 times per week (1B).

ESPEN micronutrient guideline.

BACKGROUND: Trace elements and vitamins, named together micronutrients (MNs), are essential for human metabolism. Recent research has shown the importance of MNs in common pathologies, with significant deficiencies impacting the outcome. OBJECTIVE: 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". METHODS: The expert group attempted to apply the 2015 standard operating procedures (SOP) for ESPEN which focuses on disease. However, this approach could not be applied due to the multiple diseases requiring clinical nutrition resulting in one text for each MN, rather than for diseases. An extensive search of the literature was conducted in the databases Medline, PubMed, Cochrane, Google Scholar, and CINAHL. The search focused on physiological data, historical evidence (published before PubMed release in 1996), and observational and/or randomized trials. For each MN, the main functions, optimal analytical methods, impact of inflammation, potential toxicity, and provision during enteral or parenteral nutrition were addressed. The SOP wording was applied for strength of recommendations. RESULTS: There was a limited number of interventional trials, preventing meta-analysis and leading to a low level of evidence. The recommendations underwent a consensus process, which resulted in a percentage of agreement (%): strong consensus required of >90% of votes. Altogether the guideline proposes sets of recommendations for 26 MNs, resulting in 170 single recommendations. Critical MNs were identified with deficiencies being present in numerous acute and chronic diseases. Monitoring and management strategies are proposed. CONCLUSION: This guideline should enable addressing suboptimal and deficient status of a bundle of MNs in at-risk diseases. In particular, it offers practical advice on MN provision and monitoring during nutritional support.

Sex-Specific Catabolic Metabolism Alterations in the Critically Ill following High Dose Vitamin D.

Pharmacological interventions are essential for the treatment and management of critical illness. Although women comprise a large proportion of the critically ill, sex-specific pharmacological properties are poorly described in critical care. The sex-specific effects of vitamin D3 treatment in the critically ill are not known. Therefore, we performed a metabolomics cohort study with 1215 plasma samples from 428 patients from the VITdAL-ICU trial to study sex-specific differences in the metabolic response to critical illness following high-dose oral vitamin D3 intervention. In women, despite the dose of vitamin D3 being higher, pharmacokinetics demonstrated a lower extent of vitamin D3 absorption compared to men. Metabolic response to high-dose oral vitamin D3 is sex-specific. Sex-stratified individual metabolite associations with elevations in 25(OH)D following intervention showed female-specific positive associations in long-chain acylcarnitines and male-specific positive associations in free fatty acids. In subjects who responded to vitamin D3 intervention, significant negative associations were observed in short-chain acylcarnitines and branched chain amino acid metabolites in women as compared to men. Acylcarnitines and branched chain amino acids are reflective of fatty acid B oxidation, and bioenergesis may represent notable metabolic signatures of the sex-specific response to vitamin D. Demonstrating sex-specific pharmacometabolomics differences following intervention is an important movement towards the understanding of personalized medicine.

Vitamin D deficiency in critically ill COVID-19 ARDS patients.

BACKGROUND & AIMS: Vitamin D's pleiotropic effects include immune modulation, and its supplementation has been shown to prevent respiratory tract infections. The effectivity of vitamin D as a therapeutic intervention in critical illness remains less defined. The current study analyzed clinical and immunologic effects of vitamin D levels in patients suffering from coronavirus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS). METHODS: This was a single-center retrospective study in patients receiving intensive care with a confirmed SARS-CoV-2 infection and COVID-19 ARDS. 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum levels, pro- and anti-inflammatory cytokines and immune cell subsets were measured on admission as well as after 10-15 days. Clinical parameters were extracted from the patient data management system. Standard operating procedures included the daily administration of vitamin D3 via enteral feeding. RESULTS: A total of 39 patients with COVID-19 ARDS were eligible, of which 26 were included in this study as data on vitamin D status was available. 96% suffered from severe COVID-19 ARDS. All patients without prior vitamin D supplementation (n = 22) had deficient serum levels of 25-hydroxyvitamin D. Vitamin D supplementation resulted in higher serum levels of 25-hydroxyvitamin D but not did not increase 1,25-dihydroxyvitamin D levels after 10-15 days. Clinical parameters did not differ between patients with sufficient or deficient levels of 25-hydroxyvitamin D. Only circulating plasmablasts were higher in patients with 25-hydroxyvitamin D levels ≥30 ng/ml (p = 0.029). Patients with 1,25-dihydroxyvitamin D levels below 20 pg/ml required longer mechanical ventilation (p = 0.045) and had a worse acute physiology and chronic health evaluation (APACHE) II score (p = 0.048). CONCLUSION: The vast majority of COVID-19 ARDS patients had vitamin D deficiency. 25-hydroxyvitamin D status was not related to changes in clinical course, whereas low levels of 1,25-dihydroxyvitamin D were associated with prolonged mechanical ventilation and a worse APACHE II score.

An update of the effects of vitamins D and C in critical illness.

Many critically ill patients are vitamin D and vitamin C deficient and the current international guidelines state that hypovitaminoses should be compensated. However, uncertainty about optimal dosage, timing and indication exists in clinical routine, mainly due to the conflicting evidence. This narrative review discusses both micronutrients with regards to pathophysiology, clinical evidence of benefits, potential risks, and guideline recommendations. Evidence generated from the most recent clinical trials are summarized and discussed. In addition, pragmatic tips for the application of these vitamins in the clinical routine are given. The supplementations of vitamin D and C represent cost-effective and simple interventions with excellent safety profiles. Regarding vitamin D, critically ill individuals require a loading dose to improve 25(OH)D levels within a few days, followed by a daily or weekly maintenance dose, usually higher doses than healthy individuals are needed. For vitamin C, dosages of 100-200 mg/d are recommended for patients receiving parenteral nutrition, but needs may be as high as 2-3 g/d in acutely ill patients.

Procalcitonin metabolomics in the critically ill reveal relationships between inflammation intensity and energy utilization pathways.

Procalcitonin is a biomarker of systemic inflammation and may have importance in the immune response. The metabolic response to elevated procalcitonin in critical illness is not known. The response to inflammation is vitally important to understanding metabolism alterations during extreme stress. Our aim was to determine if patients with elevated procalcitonin have differences in the metabolomic response to early critical illness. We performed a metabolomics study of the VITdAL-ICU trial where subjects received high dose vitamin D3 or placebo. Mixed-effects modeling was used to study changes in metabolites over time relative to procalcitonin levels adjusted for age, Simplified Acute Physiology Score II, admission diagnosis, day 0 25-hydroxyvitamin D level, and the 25-hydroxyvitamin D response to intervention. With elevated procalcitonin, multiple members of the short and medium chain acylcarnitine, dicarboxylate fatty acid, branched-chain amino acid, and pentose phosphate pathway metabolite classes had significantly positive false discovery rate corrected associations. Further, multiple long chain acylcarnitines and lysophosphatidylcholines had significantly negative false discovery rate corrected associations with elevated procalcitonin. Gaussian graphical model analysis revealed functional modules specific to elevated procalcitonin. Our findings show that metabolite differences exist with increased procalcitonin indicating activation of branched chain amino acid dehydrogenase and a metabolic shift.

Vitamin D in critical care: where are we now and what is next?

PURPOSE OF REVIEW: To summarize the recent evidence on the role of vitamin D deficiency in critically ill patients and emerging data claiming a role of vitamin D in COVID-19. RECENT FINDINGS: Vitamin D is a strong predictor for worse outcomes in critically ill patients, and as well in COVID-19. The vitamin D content in typical nutrition regimes is lower than what is recommended for the general population. Although its supplementation has been shown to reduce respiratory tract infections, asthma exacerbations and mortality risk in noncritically ill patients, its role in the acute setting is not yet clear. Several small intervention trials have shown interesting results in COVID-19, and larger studies are ongoing. SUMMARY: Although research on this topic is still ongoing, it appears reasonable to recommend at least the standard vitamin dose for the healthy population (600--800 IU of native vitamin D3). Many questions remain on the actual role, the best metabolite, regime, and so forth. However, the role for vitamin D in bone health is clear. Elderly ICU survivors have a high risk for osteoporosis/fractures, so at least in this population, an optimal vitamin D status should be targeted.

Metabolomic differences between critically Ill women and men.

Metabolism differs in women and men at homeostasis. Critically ill patients have profound dysregulation of homeostasis and metabolism. It is not clear if the metabolic response to critical illness differs in women compared to men. Such sex-specific differences in illness response would have consequences for personalized medicine. Our aim was to determine the sex-specific metabolomic response to early critical illness. We performed a post-hoc metabolomics study of the VITdAL-ICU trial where subjects received high dose vitamin D3 or placebo. Using mixed-effects modeling, we studied sex-specific changes in metabolites over time adjusted for age, Simplified Acute Physiology Score II, admission diagnosis, day 0 25-hydroxyvitamin D level, and 25-hydroxyvitamin D response to intervention. In women, multiple members of the sphingomyelin and lysophospholipid metabolite classes had significantly positive Bonferroni corrected associations over time compared to men. Further, multiple representatives of the acylcarnitine, androgenic steroid, bile acid, nucleotide and amino acid metabolite classes had significantly negative Bonferroni corrected associations over time compared to men. Gaussian graphical model analyses revealed sex-specific functional modules. Our findings show that robust and coordinated sex-specific metabolite differences exist early in critical illness.

Metabolomic basis for response to high dose vitamin D in critical illness.

BACKGROUND & AIMS: It is unclear if intervention can mitigate the dramatic alterations of metabolic homeostasis present in critical illness. Our objective was to determine the associations between increased 25-hydroxyvitamin D levels following high dose vitamin D3 and more favorable metabolomic profiles in critical illness. METHODS: We performed a post-hoc metabolomics study of the VITdAL-ICU randomized double-blind, placebo-controlled trial. Trial patients from Medical and Surgical Intensive Care Units at a tertiary university hospital with 25-hydroxyvitamin D level ≤20 ng/mL received either high dose oral vitamin D3 (540,000 IU) or placebo. We performed an analysis of 578 metabolites from 1215 plasma samples from 428 subjects at randomization (day 0), day 3 and 7. Using mixed-effects modeling, we studied changes in metabolite profiles in subjects receiving intervention or placebo relative to absolute increases in 25-hydroxyvitamin D levels from day 0 to day 3. RESULTS: 55.2% of subjects randomized to high dose vitamin D3 demonstrated an absolute increase in 25-hydroxyvitamin D ≥ 15 ng/ml from day 0 to day 3. With an absolute increase in 25-hydroxyvitamin D ≥ 15 ng/ml, multiple members of the sphingomyelin, plasmalogen, lysoplasmalogen and lysophospholipid metabolite classes had significantly positive Bonferroni corrected associations over time. Further, multiple representatives of the acylcarnitine and phosphatidylethanolamine metabolite classes had significantly negative Bonferroni corrected associations over time with an absolute increase in 25-hydroxyvitamin D ≥ 15 ng/ml. Changes in these highlighted metabolite classes were associated with decreased 28-day mortality. CONCLUSIONS: Increases in 25-hydroxyvitamin D following vitamin D3 intervention are associated with favorable changes in metabolites involved in endothelial protection, enhanced innate immunity and improved mitochondrial function.

Monitoring and parenteral administration of micronutrients, phosphate and magnesium in critically ill patients: The VITA-TRACE survey.

BACKGROUND & AIMS: Despite the presumed importance of preventing and treating micronutrient and mineral deficiencies, it is still not clear how to optimize measurement and administration in critically ill patients. In order to design future comparative trials aimed at optimizing micronutrient and mineral management, an important first step is to gain insight in the current practice of micronutrient, phosphate and magnesium monitoring and administration. METHODS: Within the metabolism-endocrinology-nutrition (MEN) section of the European Society of Intensive Care Medicine (ESICM), the micronutrient working group designed a survey addressing current practice in parenteral micronutrient and mineral administration and monitoring. Invitations were sent by the ESICM research department to all ESICM members and past members. RESULTS: Three hundred thirty-four respondents completed the survey, predominantly consisting of physicians (321 [96.1%]) and participants working in Europe (262 [78.4%]). Eighty-one (24.3%) respondents reported to monitor micronutrient deficiencies through clinical signs and/or laboratory abnormalities, and 148 (44.3%) reportedly measure blood micronutrient concentrations on a routine basis. Two hundred ninety-two (87.4%) participants provided specific data on parenteral micronutrient supplementation, of whom 150 (51.4%) reported early administration of combined multivitamin and trace element preparations at least in selected patients. Among specific parenteral micronutrient preparations, thiamine (146 [50.0%]) was reported to be the most frequently administered micronutrient, followed by vitamin B complex (104 [35.6%]) and folic acid (86 [29.5%]). One hundred twenty (35.9%) and 113 (33.8%) participants reported to perform daily measurements of phosphate and magnesium, respectively, whereas 173 (59.2%) and 185 (63.4%) reported to routinely supplement these minerals parenterally. CONCLUSION: The survey revealed a wide variation in current practices of micronutrient, phosphate and magnesium measurement and parenteral administration, suggesting a risk of insufficient prevention, diagnosis and treatment of deficiencies. These results provide the context for future comparative studies, and identify areas for knowledge translation and recommendations.

Morphometric parameters of muscle and bone in critically ill patients : Post hoc analysis of the VITdAL-ICU trial.

BACKGROUND: Sarcopenia, defined as loss of muscle mass, quality and function, is a part of the frailty syndrome. In critical illness, sarcopenia has rarely been evaluated regarding clinical outcomes. Therefore, we evaluated the association of sarcopenia with both hospital length of stay (HLOS) and 6­month mortality in critically ill patients using abdominal computed tomography (CT) scans. METHODS: In a post hoc analysis from the high dose vitamin D3 vs. placebo in adult vitamin D deficient patients (VITdAL-ICU) trial, we retrospectively reviewed all available abdominal CT scans (18 women, 19 men). We measured and calculated total psoas area (TPA), psoas muscle density (PMD), skeletal muscle index (SMI) and bone mineral density (BMD) and analyzed the relation of these endpoints with HLOS and mortality. Defining sarcopenia we used cut-off values for TPA as 642.1 mm2/m2 in women and 784 mm2/m2 in men and PMD as 31.1 Hounsfield units (HU) in women and 33.3 HU in men, both measured at the level of L3, as well as for SMI (38.5 cm2/m2 in women and 52.4 cm2/m2 in men). Likely osteoporosis was defined by L1 trabecular attenuation of ≤110 HU. Values for TPA, PMD and SMI could not be obtained in 11 patients and BMD in 1 patient. RESULTS: Mean adjusted TPA was lower in women versus men (478 vs. 749 mm2/m2) as well as PMD (34.6 vs. 41.3 HU), SMI (62.36 vs. 76.81 cm2/m2) and BMD (141.1 vs. 157.2 HU). No significant influence on hospital length of stay and on 6­month mortality was found, irrespective of the morphometric parameter used (TPA, PMD, SMI, BMD; p > 0.05). Survivors showed statistically nonsignificantly better values than nonsurvivors: TPA: 652 vs. 530 mm2/m2 (p = 0.27); PMD: 38.4 vs. 37.4 HU (p = 0.85); SMI: 70.32 vs. 69.54 cm2/m2 (p = 0.91); BMD: 156 vs. 145.8 HU (p = 0.81). CONCLUSION: Although the study is limited by the small sample size, our data do not support a strong predictive value for TPA/PMD/SMI or BMD for HLOS or mortality in critically ill patients with vitamin D deficiency.

Thyroid-Gut-Axis: How Does the Microbiota Influence Thyroid Function?

A healthy gut microbiota not only has beneficial effects on the activity of the immune system, but also on thyroid function. Thyroid and intestinal diseases prevalently coexist-Hashimoto's thyroiditis (HT) and Graves' disease (GD) are the most common autoimmune thyroid diseases (AITD) and often co-occur with Celiac Disease (CD) and Non-celiac wheat sensitivity (NCWS). This can be explained by the damaged intestinal barrier and the following increase of intestinal permeability, allowing antigens to pass more easily and activate the immune system or cross-react with extraintestinal tissues, respectively. Dysbiosis has not only been found in AITDs, but has also been reported in thyroid carcinoma, in which an increased number of carcinogenic and inflammatory bacterial strains were observed. Additionally, the composition of the gut microbiota has an influence on the availability of essential micronutrients for the thyroid gland. Iodine, iron, and copper are crucial for thyroid hormone synthesis, selenium and zinc are needed for converting T4 to T3, and vitamin D assists in regulating the immune response. Those micronutrients are often found to be deficient in AITDs, resulting in malfunctioning of the thyroid. Bariatric surgery can lead to an inadequate absorption of these nutrients and further implicates changes in thyroid stimulating hormone (TSH) and T3 levels. Supplementation of probiotics showed beneficial effects on thyroid hormones and thyroid function in general. A literature research was performed to examine the interplay between gut microbiota and thyroid disorders that should be considered when treating patients suffering from thyroid diseases. Multifactorial therapeutic and preventive management strategies could be established and more specifically adjusted to patients, depending on their gut bacteria composition. Future well-powered human studies are warranted to evaluate the impact of alterations in gut microbiota on thyroid function and diseases.

The Effect of Parenteral or Oral Iron Supplementation on Fatigue, Sleep, Quality of Life and Restless Legs Syndrome in Iron-Deficient Blood Donors: A Secondary Analysis of the IronWoMan RCT.

Background: Besides anemia, iron deficiency may cause more subtle symptoms, including the restless legs syndrome (RLS), the chronic fatigue syndrome (CFS) or sleeping disorders. Objective: The aim of this pre-planned secondary analysis of the IronWoMan randomized controlled trial (RCT) was to compare the frequency and severity of symptoms associated with iron deficiency before and after (intravenous or oral) iron supplementation in iron deficient blood donors. METHODS/DESIGN: Prospective, randomized, controlled, single-centre trial. (ClinicalTrials.gov: NCT01787526). SETTING: Tertiary care center in Graz, Austria. PARTICIPANTS: 176 (138 female and 38 male) whole-blood and platelet apheresis donors aged ≥ 18 and ≤ 65 years with iron deficiency (ferritin ≤ 30ng/mL at the time of blood donation). INTERVENTIONS: Intravenous iron (1 g ferric carboxymaltose, n = 86) or oral iron supplementation (10 g iron fumarate, 100 capsules, n = 90). MEASUREMENTS: Clinical symptoms were evaluated by a survey before iron therapy (visit 0, V0) and after 8-12 weeks (visit 1, V1), including questions about symptoms of restless legs syndrome (RLS), chronic fatigue syndrome (CFS), sleeping disorders, quality of life and symptoms like headaches, dyspnoea, dizziness, palpitations, pica and trophic changes in fingernails or hair. RESULTS: We found a significant improvement in the severity of symptoms for RLS, fatigue and sleep quality (p < 0.001). Furthermore, a significant decrease in headaches, dyspnoea, dizziness and palpitations was reported (p < 0.05). There was no difference between the type of iron supplementation (intravenous versus oral) and clinical outcome data. CONCLUSION: Iron supplementation in iron-deficient blood donors may be an effective strategy to improve symptoms related to iron deficiency and the wellbeing of blood donors.

Vitamin D deficiency 2.0: an update on the current status worldwide.

Vitamin D testing and the use of vitamin D supplements have increased substantially in recent years. Currently, the role of vitamin D supplementation, and the optimal vitamin D dose and status, is a subject of debate, because large interventional studies have been unable to show a clear benefit (in mostly vitamin D replete populations). This may be attributed to limitations in trial design, as most studies did not meet the basic requirements of a nutrient intervention study, including vitamin D-replete populations, too small sample sizes, and inconsistent intervention methods regarding dose and metabolites. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] < 50 nmol/L or 20 ng/ml) is associated with unfavorable skeletal outcomes, including fractures and bone loss. A 25(OH)D level of >50 nmol/L or 20 ng/ml is, therefore, the primary treatment goal, although some data suggest a benefit for a higher threshold. Severe vitamin D deficiency with a 25(OH)D concentration below <30 nmol/L (or 12 ng/ml) dramatically increases the risk of excess mortality, infections, and many other diseases, and should be avoided whenever possible. The data on a benefit for mortality and prevention of infections, at least in severely deficient individuals, appear convincing. Vitamin D is clearly not a panacea, and is most likely efficient only in deficiency. Given its rare side effects and its relatively wide safety margin, it may be an important, inexpensive, and safe adjuvant therapy for many diseases, but future large and well-designed studies should evaluate this further. A worldwide public health intervention that includes vitamin D supplementation in certain risk groups, and systematic vitamin D food fortification to avoid severe vitamin D deficiency, would appear to be important. In this narrative review, the current international literature on vitamin D deficiency, its relevance, and therapeutic options is discussed.

High-dose intravenous versus oral iron in blood donors with iron deficiency: The IronWoMan randomized, controlled clinical trial.

INTRODUCTION: Frequent blood donation often leads to iron deficiency and even anemia but appropriate strategies for detection and prevention are currently not mandatory. At the Medical University of Graz, we conducted a single-center prospective clinical trial to compare oral and IV iron supplementation in iron deficient blood donors including Austrian regular whole blood and platelet apheresis donors. We aimed to determine the difference of transferrin saturation between the treatment groups 8-12 weeks iron administration besides other parameters of iron status and blood count. METHODS: 176 healthy male and female blood donors with iron deficiency (ferritin ≤30 ng/mL) were randomized to either a single dose of IV ferric carboxymaltose (1000 mg, n = 86) or oral iron (II)fumarate (100 tablets of 100 mg [10 per week], n = 90). RESULTS: Between 2014 and 2016, 172 donors (137 women) completed the study; 4 in the oral group were lost to follow-up. At follow-up, median (IQR) transferrin saturation and ferritin were significantly higher in the intravenous group (27 [23-35]%, vs 21.0 [16-32]%; p < 0.001 and 105 [75-145] ng/mL vs 25 [17-34] ng/mL; p < 0.001, respectively) while median (IQR) hemoglobin levels were comparable (IV, 13.6 [13.0-14.4] g/dL vs oral, 13.6 [13.0-14.2] g/dL). The frequency of adverse effects was comparable (38% in both groups) and no serious adverse events occurred. CONCLUSIONS: A single dose of 1000 mg of intravenous iron is highly effective to counteract iatrogenic iron deficiency in blood donors. Oral iron appears to be an acceptable alternative. The assessment of body iron stores should play a key role in maintaining blood donors' health. This trial was registered at www.clinicaltrials.gov as NCT01787526 on February 8, 2013 and at www.clinicaltrialsregister.eu (EudraCT identifier: 2013-000327-14) on September 24, 2013.

Effect of high-dose vitamin D3 on 28-day mortality in adult critically ill patients with severe vitamin D deficiency: a study protocol of a multicentre, placebo-controlled double-blind phase III RCT (the VITDALIZE study).

INTRODUCTION: Observational studies have demonstrated an association between vitamin D deficiency and increased risk of morbidity and mortality in critically ill patients. Cohort studies and pilot trials have suggested promising beneficial effects of vitamin D replacement in the critical ill, at least in patients with severe vitamin D deficiency. As vitamin D is a simple, low-cost and safe intervention, it has potential to improve survival in critically ill patients. METHODS AND ANALYSIS: In this randomised, placebo-controlled, double-blind, multicentre, international trial, 2400 adult patients with severe vitamin D deficiency (25-hydroxyvitamin D≤12 ng/mL) will be randomised in a 1:1 ratio by www.randomizer.at to receive a loading dose of 540 000 IU cholecalciferol within 72 hours after intensive care unit (ICU) admission, followed by 4000 IU daily for 90 days or placebo. Hypercalcaemia may occur as a side effect, but is monitored by regular checks of the calcium level. The primary outcome is all-cause mortality at 28 days after randomisation. Secondary outcomes are: ICU, hospital, 90-day and 1-year mortality; hospital and ICU length of stay, change in organ dysfunction on day 5 as measured by Sequential Organ Function Assessment (SOFA) score, number of organ failures; hospital and ICU readmission until day 90; discharge destination, self-reported infections requiring antibiotics until day 90 and health-related quality of life. Recruitment status is ongoing. ETHICS AND DISSEMINATION: National ethical approval was obtained by the Ethics Committee of the University of Graz for Austria, Erasme University Brussels (Belgium) and University Hospital Frankfurt (Germany), and will further be gained according to individual national processes. On completion, results will be published in a peer-reviewed scientific journal. The study findings will be presented at national and international meetings with abstracts online. TRIAL REGISTRATION: NCT03188796, EudraCT-No: 2016-002460-13.