Impact of Vitamin D Supplementation on Hepcidin Levels and Transfusion Requirements in Surgical and Septic Patients (DEHEPTRA)

February 3, 2017 updated by: Cristina Petrisor, Iuliu Hatieganu University of Medicine and Pharmacy

Impact of Vitamin D Enteral Supplementation on Hepcidin Serum Levels and Transfusion Requirements in Surgical and Critically Ill Patients

Acute inflammation induced by surgery and sepsis is complicated by the development of iron-restricted anemia due to the up-regulation of hepcidin. Excess hepcidin causes intracellular sequestration of iron, decreasing its availability for erythropoiesis. Hepcidin might be a potential target to reduce transfusion requirements in surgical and sepsis patients. Vitamin D supplementation might constitute a novel strategy to modulate the hepcidin-ferroportin-iron axis. Up to now, there are no data regarding the possibility that by using vitamin D supplementation in surgical and septic shock patients, the physicians could ameliorate anemia and, hence, reduce transfusion requirements. Aim: to conduct a randomised controlled trial to determine the impact of high-dose vitamin D enteral supplementation on serum hepcidin levels and transfusion requirements after major abdominal surgery and in septic shock patients.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Patient blood management has become an important concept for the perioperative care of the surgical patients and in septic patients, aiming to improve outcomes. Hepcidin might be a potential target to reduce transfusion requirements after major abdominal surgery and in patients with sepsis. Major surgery and sepsis induce complex immune dysregulations, characterised by a pro-inflammatory state (the postoperative acute-phase reaction). Excess hepcidin values in acute inflammatory conditions might represent an exaggerated response that leads to iron-sequestration anemia, a functional iron deficiency anemia. Vitamin D supplementation might constitute a novel strategy to modulate the hepcidin-ferroportin-iron axis in surgery and sepsis-induced acute inflammation. Thus, vitamin D might impact hepcidin values and might reduce transfusion requirements.

I. Inflammation-induced regulation of the hepcidin-ferroportin-iron axis

Surgery and sepsis are associated with iron-restricted anemia. After major abdominal surgery and sepsis, a prototypical inflammatory syndrome, often complicated by the development of anemia, appears. Inflammatory cytokines (like interleukin 6) released during acute infection alter iron metabolism by inducing excess synthesis of hepcidin. Anemia after major abdominal surgery and sepsis may be the expression of impaired erythropoiesis as a result of hepcidin up-regulation. Hepcidin plays a role in the development of anemia, together with the inhibition of erythropoietin production, a decreased lifespan of erythrocytes, and a blunted erythropoietic response. Functional iron deficiency is increasingly recognised as a cause of anemia in the general surgical patient and in patients with sepsis.

Iron is a two-faced element. First, iron is essential for living as it is incorporated in the "breathing" molecule haemoglobin and in the mitochondrial respiratory chain. On the other hand, iron is detrimental due to the generation of oxidative stress and its availability for the growing of bacteria. Low serum iron level is considered detrimental as it leads to anemia and low tissue oxygen delivery. Iron deficiency and anemia are associated with poor outcomes in surgical and septic patients. Also, transfusion is associated with immune suppression and other adverse reactions. Thus, other approaches to the correction of anemia are advocated, even though not yet included in the clinical practice.

Hepcidin is the master regulator of iron metabolism and hence, a modulator of anemia in states of inflammation. Hepcidin is an acute phase protein synthetised in the liver and which acts as an hyposideremia inducing hormone. It binds to ferroportin (an iron exporter) and prevents the release of iron from the cells: prevents the absorption of dietary iron from enterocytes and prevents iron release from macrophages, where it is stored. Thus, the effect of hepcidin would be iron sequestration, lowering the serum iron concentrations. The beneficial result would be a low availability of iron for bacterial growth (thus, a direct antimicrobial effect) and less oxidative stress. The detrimental result is the limited possibility for the synthesis of new haemoglobin molecules and the occurrence of anemia. The up-regulation of hepcidin, as a pro-inflammatory biomarker, characterises both acute and chronic inflammatory conditions. The induction of hepcidin synthesis may be the cause for the iron-restricted erythropoiesis in the surgical population and in patients with sepsis. The induction of hepcidin synthesis may contribute to the development of anemia, which is detrimental for tissue oxygenation and might increase transfusion requirements and the aggravation of immune suppression after blood transfusion. In animal models of anemia due to inflammation, hepcidin knockout mice had milder anemia and faster recovery.

Excess values of the iron regulating hormone hepcidin causes intracellular sequestration of iron and might decrease the availability of iron for erythropoiesis, leading to the anemia frequently encountered in inflammatory conditions. Anemia is not only very frequent among critically ill patients, but is associated with increased transfusion rates and worse outcomes. Anemia may impair oxygen delivery to peripheral tissues and impose transfusion, which itself carries the risk of further immune suppression. Recent data has emphasised the need to restrict transfusions as much as possible, as transfusion is associated with increased morbidity and mortality. Instead, alternative methods to improve anemia and ameliorate tissue oxygen delivery might be beneficial.

II. Vitamin D down-regulates hepcidin expression

Vitamin D is a hormone promoting bone health, which also has a wide range of cellular activities including the differentiation of hematopoietic cells and down-regulation of inflammatory cytokines. Vitamin D has anti-inflammatory and immune-regulating properties and the maintenance of adequate vitamin D status may play a role in managing inflammation and immunity. Vitamin D supplementation in patients with chronic inflammatory conditions like chronic kidney disease improves the values of circulating markers of inflammation and immunity. Recently, it has been highlighted that in certain conditions, like chronic kidney disease, the administration of vitamin D reduces serum hepcidin values and transfusion requirements.

Up to now, there are no data regarding the possibility that by using vitamin D supplementation in surgical or septic shock patients, the physicians could target the hepcidin-ferroportin-iron axis to prevent the occurrence of anemia and, hence, reduce transfusion requirements. Oral vitamin D supplementation lowers hepcidin values and might increase erythropoiesis and decrease inflammation.

III. Vitamin D supplementation in the critically ill. Safety profile

The therapeutic potential of vitamin D is a topic of intense interest. A high prevalence of low vitamin D levels has been confirmed in patients who are critically ill. Vitamin D deficiency is associated with higher infection rates, 30-day mortality and in-hospital mortality in adult critically ill patients. During critical illness, vitamin D supplementation has a favorable safety profile and a possible mechanism of vitamin D supplementation in inducing bactericidal pleiotropic effects has been suggested. To improve vitamin D status, high-dose vitamin D is required in the critically ill, as they display a blunted response to supplementation. Recent evidence suggests that treatment of vitamin-D deficient critically ill patients may improve outcomes and mortality, possibly through enhancing innate immunity and the inhibition of proinflammatory cytokines. Further clinical trials to explore the effects of vitamin D supplementation on the up-regulation process of proinflammatory cytokines are needed.

Study Type

Interventional

Enrollment (Anticipated)

40

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Romania
    • Cluj
      • Cluj-napoca, Cluj, Romania, 400012
        • Recruiting
        • Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • sepsis and septic shock patients
  • patients with major abdominal surgery

Exclusion Criteria:

  • chronic inflammatory conditions (chronic kidney disease, hematologic, and rheumatic/autoimmune disease)
  • morbid obesity (BMI over 40kg/m2)
  • pregnancy and lactation
  • hypercalcemia (total calcium> 10.6mg/dL, serum ionized calcium>5.4mg/dL)
  • tuberculosis, sarcoidosis
  • nephrolithiasis
  • recent history of vitamin D supplementation or erythropoietin

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: vitamin D +
Patients in the "vitamin D" group will receive enteral supplementation with vitamin D, blood collection 3mL is performed in the first 24 hours after admission and one week later for serum hepcidin measurement
Dietary supplement: enteral supplementation with vitamin D
Patients allocated to the "vitamin D +" group receive enteral supplementation with high-dose vitamin D (250.000UI)
Other: blood collection 3mL
all patients will have hepcidin levels measured in the first 24 hours after admission and one week after
Placebo Comparator: vitamin D -
Patients in "vitamin D -" group do not receive enteral supplementation with vitamin D and represent the control group, blood collection 3mL is performed in the first 24 hours after admission and one week later for serum hepcidin measurement
Other: blood collection 3mL
all patients will have hepcidin levels measured in the first 24 hours after admission and one week after

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hepcidin concentration (ng/mL)
Time Frame: one week after intervention
Hepcidin serum concentrations measured one week after the intervention
one week after intervention

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Packed red cells
Time Frame: two weeks after intervention
The number of transfused packed red cells in the first two weeks after the intervention
two weeks after intervention

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Iuliu Hatieganu University of Medicine and Pharmacy

Investigators

  • Principal Investigator: Cristina Petrisor, MD, PhD, University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2017

Primary Completion (Anticipated)

June 1, 2017

Study Completion (Anticipated)

December 1, 2017

Study Registration Dates

First Submitted

December 13, 2016

First Submitted That Met QC Criteria

December 20, 2016

First Posted (Estimate)

December 23, 2016

Study Record Updates

Last Update Posted (Estimate)

February 6, 2017

Last Update Submitted That Met QC Criteria

February 3, 2017

Last Verified

December 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 434/24.11.2016

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

Only on request

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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