cholecalciferol and Sepsis

Despite a decrease in mortality over the last decade, sepsis remains the tenth leading causes of death in western countries and one of the most common cause of death in intensive care units. The recent discovery of Toll-like receptors and their downstream signalling pathways allowed us to better understand the pathophysiology of sepsis-related disorders. Particular attention has been paid to Toll-like receptor 4, the receptor for Gram-negative bacteria outer membrane lipopolysaccharide or endotoxin. Since most of the clinical trial targeting single inflammatory cytokine in the treatment of sepsis failed, therapeutic targeting of Toll-like receptor 4, because of its central role, looks promising. The purpose of this paper is to focus on the recent data of various drugs targeting TLR4 expression and pathway and their potential role as adjunctive therapy in severe sepsis and septic shock.

Topics: Analgesics; Analgesics, Opioid; Animals; Antibodies; Antirheumatic Agents; Chloroquine; Cholecalciferol; Disaccharides; Ganglionic Stimulants; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ketamine; Lymphocyte Antigen 96; Nicotine; Sepsis; Sugar Phosphates; Sulfonamides; Toll-Like Receptor 4

To assess the effects of a single dose of vitamin D on 25-hydroxyvitamin D (25OHD) levels and clinical outcomes in children with vitamin D deficiency (VDD) and sepsis.. In this randomized, controlled trial, eligible children with VDD and sepsis were assigned to receive one dose of 150,000 IU of cholecalciferol or placebo. Serum concentrations of 25OHD, angiotensin-II (Ang-II), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were assessed at baseline and 8 days after treatment. The cardiovascular Sequential Organ Failure Assessment (cv-SOFA) score, septic shock incidence, duration of ventilation, and mortality were also examined.. One hundred nine participants fulfilled the study requirements. The two groups had comparable baseline characteristics. Ang-II, IL-6, and TNF-α concentrations were all reduced after vitamin D supplementation. Furthermore, the cv-SOFA score (1.76 ± 0.8 vs. 2.3 ± 1.1) and incidence of septic shock (7% vs. 20%) were lower in the treatment group than in the control group. The duration of ventilation and mortality rates did not differ between two groups.. A single dose of vitamin D improved 25OHD levels and the incidence of septic shock in children with VDD and sepsis.

Topics: Administration, Oral; Child; Child, Preschool; Cholecalciferol; Double-Blind Method; Female; Humans; Incidence; Infant; Male; Organ Dysfunction Scores; Prospective Studies; Sepsis; Severity of Illness Index; Shock, Septic; Treatment Outcome; Vitamin D; Vitamin D Deficiency

To evaluate biochemical and clinical effects of 2 different doses of vitamin D supplementation in preterm infants with late-onset sepsis (LOS).. A double blinded randomized controlled stratified trial included preterm infants with gestational age (GA) ≥28 weeks with LOS. Subjects were randomly assigned to receive 400 or 800 IU/day of vitamin D3. Serum concentrations of 25(OH)D, TNF-α, and IL-6 were measured at enrollment, 7 days after vitamin D supplementation, and at 40 weeks of postmenstrual age (PMA). Short-term outcomes and growth parameters were assessed.. A total of 50 infants were enrolled, 25 in each group. Seventy-six percentage of enrolled infants were vitamin D-deficient at enrollment in both groups whereas only one infant in the 400 IU and none in the 800 IU group remained deficient at 40 week's PMA; vitamin D concentrations at 40 weeks PMA were 54.8 ± 35.1 and 67.4 ± 37.1 ng/mL, respectively, P = 0.01). None of the infants enrolled in the study had signs of vitamin D toxicity. Serum pro-inflammatory cytokines IL-6 and TNF- α concentrations decreased at 1 week and at discharge in both groups without differences between groups. The 2 groups did not differ in anthropometric measurements, duration of oxygen and respiratory support, duration of antimicrobial use, length of hospital stay, and mortality.. A dose of 400 IU of vitamin D was adequate to treat vitamin D deficiency in the majority of premature infants with LOS. The 2 dosing regimens did not differ in clinical or biochemical changes.

Topics: Administration, Oral; Cholecalciferol; Dietary Supplements; Double-Blind Method; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Interleukin-6; Male; Sepsis; Treatment Outcome; Tumor Necrosis Factor-alpha; Vitamin D

To compare changes in vitamin D status and cathelicidin (LL-37) levels in septic ICU patients treated with placebo versus cholecalciferol.. Randomized, placebo-controlled, trial.. Medical and surgical ICUs of a single teaching hospital in Boston, MA.. Thirty adult ICU patients.. Placebo (n = 10) versus 200,000 IU cholecalciferol (n = 10) versus 400,000 IU cholecalciferol (n = 10), within 24 hours of new-onset severe sepsis or septic shock.. Blood samples were obtained at baseline (day 1) and on days 3, 5, and 7, to assess total 25-hydroxyvitamin D, as well as vitamin D-binding protein and albumin to calculate bioavailable 25-hydroxyvitamin D. Plasma LL-37 and high-sensitivity C-reactive protein levels were also measured. At baseline, median (interquartile range) plasma 25-hydroxyvitamin D was 17 ng/mL (13-22 ng/mL) and peaked by day 5 in both intervention groups. Groups were compared using Kruskal-Wallis tests. Relative to baseline, on day 5, median change in biomarkers for placebo, 200,000 IU cholecalciferol, and 400,000 IU cholecalciferol groups, respectively, were as follows: 1) total 25-hydroxyvitamin D, 3% (-3% to 8%), 49% (30-82%), and 69% (55-106%) (p < 0.001); 2) bioavailable 25-hydroxyvitamin D, 4% (-8% to 7%), 45% (40-70%), and 96% (58-136%) (p < 0.01); and 3) LL-37: -17% (-9% to -23%), 4% (-10% to 14%), and 30% (23-48%) (p = 0.04). Change in high-sensitivity C-reactive protein levels did not differ between groups. A positive correlation was observed between bioavailable 25-hydroxyvitamin D and LL-37 (Spearman ρ = 0.44; p = 0.03) but not for total 25-hydroxyvitamin D and LL-37.. High-dose cholecalciferol supplementation rapidly and safely improves 25-hydroxyvitamin D and bioavailable 25-hydroxyvitamin D levels in patients with severe sepsis or septic shock. Changes in bioavailable 25-hydroxyvitamin D are associated with concomitant increases in circulating LL-37 levels. Larger trials are needed to verify these findings and to assess whether optimizing vitamin D status improves sepsis-related clinical outcomes.

Topics: Adult; Antimicrobial Cationic Peptides; Biomarkers; C-Reactive Protein; Calcifediol; Cathelicidins; Cholecalciferol; Dietary Supplements; Female; Hospitals, Teaching; Humans; Intensive Care Units; Male; Middle Aged; Sepsis; Serum Albumin; Shock, Septic; Vitamin D

Vitamin D deficiency is a global public health problem, a pandemic that commonly affects the elderly and those with comorbidities such as obesity, diabetes, hypertension, respiratory disorders, recurrent infections, immune deficiency, and malignancies, as well as ethnic minorities living in temperate countries. The same groups were worst affected by COVID-19. Since vitamin D deficiency weakens the immune system, it increases the risk of infections, complications, and deaths, such as from sepsis and COVID-19. Deficiency can be remedied cost-effectively through targeted food fortification, supplementation, and/or daily safe sun exposure. Its endocrine functions are limited to mineral metabolism, musculoskeletal systems, specific cell membrane interactions, and parathyroid gland functions. Except for the rapid, endocrine, and cell membrane-based non-genomic functions, all other biological and physiological activities of vitamin D depend on the adequate intracellular synthesis of 1,25(OH)2D (calcitriol) in peripheral target cells via the genome. Calcitriol mediates autocrine (intracrine) and paracrine signalling in immune cells, which provides broader, protective immune functions crucial to overcoming infections. The synthesis of 1,25(OH)2D (calcitriol) in peripheral target cells is dependent on diffusion and endocytosis of D3 and 25(OH)D from the circulation into them, which requires maintenance of serum 25(OH)D concentration above 50 ng/mL. Therefore, in acute infections such as sepsis and respiratory infections like COVID-19, it is necessary to rapidly provide its precursors, D3 and 25(OH)D, through the circulation to generate adequate intracellular calcitriol. Immune defence is one of the crucial non-hormonal functions of vitamin D. A single oral (bolus) dose or divided upfront loading doses between 100,000 and 500,000 IU, using 50,000 IU vitamin D3 increase the serum 25(OH)D concentrations to a therapeutic level of above 50 ng/mL that lasts between two to three months. This takes three to five days to raise serum 25(OH)D. In contrast, a single oral dose of calcifediol (0.014 mg/kg body weight) can generate the needed 25(OH)D concentration within four hours. Considering both D3 and 25(OH)D enter immune cells for generating calcitriol, using the combination of D3 (medium-term) and calcifediol (immediate) is cost-effective and leads to the best clinical outcome. To maximise protection against infections, particularly to reduce COVID-19-associated complicati

Topics: Aged; Calcifediol; Calcitriol; Cholecalciferol; COVID-19; Dietary Supplements; Humans; Immune System; Sepsis; Vitamin D; Vitamin D Deficiency; Vitamins

In burn patients, vitamin D has been studied primarily in the pediatric population and focused mainly on the correlation with bone marker measurements and incidence of fractures. There is an association between vitamin D deficiency and the development of sepsis in non-burn critically-ill patients. However, there is limited data on vitamin D concentrations and clinical outcomes in burn patients, such as sepsis. The objective of this study is to evaluate the impact of vitamin D concentrations on the incidence of sepsis in adult burn patients.. This was a retrospective cohort of patients 18 years of age and older admitted between February 1, 2016 and February 28, 2018 to an American Burn Association (ABA) verified burn center with diagnosis of burn injury. The primary endpoint was incidence of sepsis using the ABA 2007 Sepsis Consensus Criteria between patients with adequate vitamin D concentrations (25[OH]D > 20 ng/mL) and insufficient vitamin D (25[OH]D < 20 ng/mL) concentrations measured on admission. Descriptive statistics were used for baseline demographics. Univariate analysis was conducted using Chi-square, Fisher's exact test or Mann-Whitney U test, as appropriate.. A total of 115 patients were screened and 107 patients were included in this study. Sixty three patients (58.9%) had insufficient vitamin D concentrations. Patient demographics were overall similar between groups. The median total body surface area burned was 14.6% in the insufficient vitamin D group, and 12.1% in the adequate vitamin D group (p = 0.2). There was a trend towards greater incidence of sepsis in the insufficient vitamin D group in the univariate analysis (15.9% vs. 4.5%, p = 0.07). The multivariable logistic regression analysis found that adequate vitamin D concentrations was associated with a reduction in the incidence of sepsis (OR 0.10, 95% CI 0.01-0.88). The insufficient vitamin D group had a longer median hospital LOS (19 [IQR 11-37] vs 11.5 [IQR 7-20] days, p < 0.05), longer intensive care unit LOS (17 [IQR 10-37] vs 5 [IQR 2-19.5] days, p < 0.05) and fewer ventilator free days (26 [IQR 18-28] vs 28 [IQR 27-28] days, p < 0.05). There was no difference in mortality between groups (p = 0.69).. Patients with adequate vitamin D concentrations on admission had a reduction in the incidence of sepsis as compared to patients with insufficient vitamin D concentrations. Insufficient vitamin D concentrations may contribute to other worsened clinical outcomes in burn patients. Our findings set the stage for future, multicenter studies to determine the role of vitamin D supplementation in burn patients.

Topics: Adult; Body Surface Area; Burns; Case-Control Studies; Cholecalciferol; Cohort Studies; Ergocalciferols; Female; Hospital Mortality; Humans; Incidence; Intensive Care Units; Length of Stay; Male; Middle Aged; Respiration, Artificial; Retrospective Studies; Risk Factors; Sepsis; Vitamin D; Vitamin D Deficiency; Vitamins

Vitamin D has immunomodulating properties.. To determine if vitamin D deficiency within 30 days of admission to the intensive care unit in patients with sepsis might be associated with increased all-cause 30-day mortality.. In a retrospective cohort study at a large, tertiary, urban, academic medical center, records of patients who had 25-hydroxyvitamin D levels measured within 30 days of admission for severe sepsis or septic shock from June 2006 to April 2011 were examined. Patients were considered deficient in vitamin D if its serum concentration was 15 ng/mL or less. The primary outcome of interest was 30-day mortality.. Among the 121 patients in the sample, 65 (54%) were vitamin D deficient. Baseline demographics were similar between vitamin D deficient and nondeficient groups, except that the vitamin D deficient group had more African Americans (P = .01). All-cause 30-day mortality was significantly higher in patients deficient in vitamin D (37% vs 20%; P = .04) and remained higher at 90 days (51% vs 25%, P = .005). In multivariate analysis, age (odds ratio, 1.04; 95% CI 1.01-1.07; P = .01) and vitamin D deficiency (odds ratio, 2.7; 95% CI, 1.39-18.8; P = .02) were independently associated with increased 30-day mortality.. Patients deficient in vitamin D within 30 days of hospital admission for severe sepsis or septic shock may be at increased risk for all-cause 30-day mortality.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Black or African American; Cholecalciferol; Ergocalciferols; Female; Humans; Male; Middle Aged; Retrospective Studies; Sepsis; Severity of Illness Index; Shock, Septic; Time Factors; Vitamin D; Vitamin D Deficiency; Vitamins; White People

1Alpha,25-dihydroxyvitamin D3 (active form of vitamin D3; vitamin D3) has been reported to induce the upregulation of thrombomodulin and downregulation of tissue factor (TF) on monocytes. The possibility exists that vitamin D3 prevents the development of disseminated intravascular coagulation (DIC). In particular, monocyte TF production plays an important role in the pathophysiology of DIC in septic patients. We have attempted to determine whether vitamin D3 is effective against DIC in a rat model induced by lipopolysaccharides (LPS) (30 mg/kg, 4 h) or TF (3.75 U/kg, 4 h) using selective hemostatic parameters, markers of organ dysfunction and pathological findings (assessment of glomelular fibrin deposition). Vitamin D3 was administered orally each day at a dose of 2.0 mg/kg/day for 3 days, or low molecular weight heparin (LMWH 200 u/kg; i.v.) was given 10 min before the injection of TF or LPS in each treatment group. Vitamin D3 was effective against DIC in the rat model induced by LPS only, whereas LMWH was effective against DIC in both rat models induced by either TF or LPS. The anti-DIC effect of vitamin D3 was equal to (or more potent than) that of LMWH. The results suggested that vitamin D3 was useful for the treatment of LPS-induced DIC, and that the assessment of a drug's efficacy should be done carefully given the markedly different results obtained according to the agents used to induce DIC.

Topics: Administration, Oral; Animals; Anticoagulants; Cholecalciferol; Coagulants; Disease Models, Animal; Disseminated Intravascular Coagulation; Fibrin; Heparin; Kidney Diseases; Kidney Glomerulus; Lipopolysaccharides; Male; Rats; Rats, Wistar; Sepsis; Thromboplastin; Thrombosis