The Impact of Selective Vitamin D Receptor Activation on Clinical Outcomes in Septic Patients -a Randomised Placebo Controlled Trial
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 90
- 主要终点
- survival (days)
研究概览
简要总结
Sufficient serum levels of vitamin D are important for immune system regulation with protective effect against severe infection and overactivated inflammatory response in sepsis. It is also not clear what level of vitamin D in the blood would be the trigger for vitamin D administration. A more selective approach to VDR activation than cholecalciferol could have a more significant role in the clinical outcomes of patients with sepsis. A study demonstrated that low baseline serum level of vitamin D receptor (VDR) was associated with a high incidence of 28-day mortality and negatively correlated with lactate, C-reactive protein, APACHE II SOFA scores, and disease severity among patients with sepsis in an ICU setting.
The role of selective vitamin D receptor activation agents (paricalcitol or maxacalcitol) was not studied in septic patients, despite its anti-inflammatory and immunomodulatory properties. Vitamin D analogs have different effects on nuclear VDRs than does calcitriol, through different response elements in various target genes, so it is possible that their effect on a patient with sepsis will be more effective than cholecalciferol. As distribution of VDRs is ubiquitous in many organs and tissues, selective VDR activation with paricalcitol may have beneficial effects in preserving organs functionality and modulating the immune response in sepsis.
Hypotheses
- The immunoregulatory, anti-inflammatory, and anti-oxidative properties of selective vitamin D receptor activator paricalcitol would result in improvement of inflammatory, endothelial function, and antioxidative parameters and clinical outcomes in groups of septic patient admitted to ICU.
- The baseline septic patient serum 25(OH) D3 levels at admission time in ICU have influence on clinical outcomes as well as on inflammatory, endothelial function, and antioxidative parameters.
- The inflammatory, endothelial function, and antioxidative parameters measured at ICU admission time have significant impact on clinical outcomes in septic patients.
The aim
The main objective of study is to test hypothesis that that selective activator of vitamin D receptors paricalcitol will improve outcomes of septic patient admitted in ICU. The study aims to investigate the effects of paricalcitol on clinical outcomes, inflammatory markers, organ dysfunction, endothelial function, vascular morphology, coagulation markers, and haemodynamic parameters.
The additional objectives of the study are to test hypothesis that septic patient serum 25(OH)vitamin D3 have impact on inflammatory, endothelial function, and antioxidative parameters including protein carbonylation; and to test hypothesis that these markers and clinical outcomes are interconnected with significant impact on clinical outcomes.
详细描述
There are evidences that decreased vitamin D levels among septic patients shown significant associations with adverse outcomes.
The large PETAL-VIOLET trial was conducted in 44 hospitals in the United States and enrolled 1358 severe patients (more than 80% were admitted to the ICU for medical diseases) with vitamin D deficiency. Study protocol included very early vitamin D3 supplementation (a single enteral dose of 540,000 IU) in critically ill. Results showed that early high dose of vitamin D3 supplementation had no advantage over placebo with respect to 90 day mortality or hospital stay, and found no differences between the groups of participants.
Second large study, VITdAL-ICU randomized clinical trial, was conducted among 492 critically ill adult patients with vitamin D deficiency (≤20 ng/mL) assigned to receive either vitamin D3 given orally or via nasogastric tube once at a dose of 540,000 IU followed by monthly maintenance doses of 90,000 IU for 5 months; or a placebo. There was no difference between groups in length of hospital stay, hospital mortality, and 6-month mortality. In severe vitamin D deficiency (≤12 ng/mL) subgroup analysis, only hospital mortality was significantly lower for vitamin D3 receivers.
A recent metaanalysis included 11 randomized control trials with a total of 2187 patients concluded that vitamin D supplementation in critically ill patients decreases the duration of mechanical ventilation and ICU stay. There was no significant difference noted in mortality and length of hospital stay.
Many of these studies on ICU population included mixed ICU population, including also septic patients. Only minority of studies was conducted and dedicated exclusively for septic population. VITdAL-ICU and PETAL-VIOLET trials included critically ill patients with a low prevalence of sepsis at the enrolment time (7.7% and 33.3%), so sepsis subgroup analyses did not allow clear conclusion on the efficacy of vitamin D supplementation in septic patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The participants of this study will be patients:
- •admitted as sepsis in a medical ICU. The including criteria for sepsis will be defined according The Third International Consensus Definitions for Sepsis and Septic Shock. The sepsis will be defined as suspected infection with SOFA score>=
- •The subgroup of participants with septic shock will be defined as sepsis with vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L despite adequate fluid resuscitation.
排除标准
- •total serum calcium ≥2.60 mmol/L,
- •significant chronic end stage heart, kidney or liver disease
- •active treatment with corticosteroids or cytotoxic drugs
- •autoimmune diseases
- •malignancies
- •previously been on active vitamin D therapy the last four months prior to the study period.
研究组 & 干预措施
paricalcitol group
干预措施: Paricalcitol injection (Drug)
placebo group
干预措施: Placebo (Drug)
结局指标
主要结局
survival (days)
时间窗: 7. and the 28. day
次要结局
- concentration of creatinin (umol/L) from venous blood specimen(0. and the 7. day)
- concentration of D-dimers (mg/L)from venous blood specimen(0. and the 7. day)
- leucocytes count from venous blood specimen(0. and the 7. day)
- Non-invasive assessments of Arterial Stiffness-pulse wave velocity-pulse wave velocity(0. and the 7. day)
- SAPS (Simplified Acute Physiology Score)(0., 5. and 7. day)
- coagulation parameters from venous blood specimen- activated partial thromboplastin time(0. and the 7. day)
- Oxidative stress(7.day)
- MAP (mean arterial pressure)(0., 5. and 7. day)
- Non-invasive assessments of Arterial Stiffness-Central Augmentation Index(0. and the 7. day)
- blood gasses analysis(0. and the 7. day)
- ultrasound of the spleen (B-mode)(0. and the 7. day)
- days of ICU treatment(7. day)
- haematology parameters from venous blood specimen-plateless count(0. and the 7. day)
- Sequential Organ Failure Assessment (SOFA)(0., 5. and 7. day)
- concentration of ferritin (mg/L)from venous blood specimen(0. and the 7. day)
- coagulation parameters from venous blood specimen-prothrombin time(0. and the 7. day)
- Intrarenal arteries spectral analysis: assesment of vascular resistence (RI-resistance index)(0. and the 7. day)
- concentration of calcium (mmol/L)from venous blood specimen(0. and the 7. day)
- concentration of phosphorus (mmol/L)from venous blood specimen(0. and the 7. day)
- concentration of total cholesterol (mmol/L)from venous blood specimen(0. and the 7. day)
- concentration of high-density lipoprotein (HDL)-cholesterol (mmol/L)from venous blood specimen(0. and the 7. day)
- concentration of C-reactive protein (CRP) (mg/L)from venous blood specimen(0. and the 7. day)
- concentration of serum 25(OH)D3 (nmol/l)from venous blood specimen(0. and the 7. day)
- Assessment of endothelial function(0. and the 7. day)
- concentration of troponin-I (mmol/L)from venous blood specimen(0. and the 7. day)
- concentration of iPTH (nmol/L)from venous blood specimen(0. and the 7. day)
- concentration of fibrinogen (mg/L)from venous blood specimen(0. and the 7. day)
- concentration of lactate (mmol/L)from arterial blood specimen(0. and the 7. day)
- Ultrasound measurement of quadriceps muscle thickness(0. and the 7. day)
- concentration of albumins (g/L)from venous blood specimen(0. and the 7. day)
- concentration of bicarbonate(mmol/L)from arterial blood specimen(0. and the 7. day)
- concentration of NT-proB-type natriuretic peptide (NT-proBNP) (mmol/L)from venous blood specimen(0. and the 7. day)
- concentration of procalcitonin (PCT) (mg/mL)from venous blood specimen(0. and the 7. day)
研究者
Vedran Kovacic
Profesor of Medicine
University of Split, School of Medicine