Sepsis Clinical Trial
Official title:
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.
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.
;
Status | Clinical Trial | Phase | |
---|---|---|---|
Active, not recruiting |
NCT05095324 -
The Biomarker Prediction Model of Septic Risk in Infected Patients
|
||
Completed |
NCT02714595 -
Study of Cefiderocol (S-649266) or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens
|
Phase 3 | |
Completed |
NCT03644030 -
Phase Angle, Lean Body Mass Index and Tissue Edema and Immediate Outcome of Cardiac Surgery Patients
|
||
Completed |
NCT02867267 -
The Efficacy and Safety of Ta1 for Sepsis
|
Phase 3 | |
Completed |
NCT04804306 -
Sepsis Post Market Clinical Utility Simple Endpoint Study - HUMC
|
||
Recruiting |
NCT05578196 -
Fecal Microbial Transplantation in Critically Ill Patients With Severe Infections.
|
N/A | |
Terminated |
NCT04117568 -
The Role of Emergency Neutrophils and Glycans in Postoperative and Septic Patients
|
||
Completed |
NCT03550794 -
Thiamine as a Renal Protective Agent in Septic Shock
|
Phase 2 | |
Completed |
NCT04332861 -
Evaluation of Infection in Obstructing Urolithiasis
|
||
Completed |
NCT04227652 -
Control of Fever in Septic Patients
|
N/A | |
Enrolling by invitation |
NCT05052203 -
Researching the Effects of Sepsis on Quality Of Life, Vitality, Epigenome and Gene Expression During RecoverY From Sepsis
|
||
Terminated |
NCT03335124 -
The Effect of Vitamin C, Thiamine and Hydrocortisone on Clinical Course and Outcome in Patients With Severe Sepsis and Septic Shock
|
Phase 4 | |
Recruiting |
NCT04005001 -
Machine Learning Sepsis Alert Notification Using Clinical Data
|
Phase 2 | |
Completed |
NCT03258684 -
Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Sepsis and Septic Shock
|
N/A | |
Recruiting |
NCT05217836 -
Iron Metabolism Disorders in Patients With Sepsis or Septic Shock.
|
||
Completed |
NCT05018546 -
Safety and Efficacy of Different Irrigation System in Retrograde Intrarenal Surgery
|
N/A | |
Completed |
NCT03295825 -
Heparin Binding Protein in Early Sepsis Diagnosis
|
N/A | |
Not yet recruiting |
NCT06045130 -
PUFAs in Preterm Infants
|
||
Not yet recruiting |
NCT05361135 -
18-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in S. Aureus Bacteraemia
|
N/A | |
Not yet recruiting |
NCT05443854 -
Impact of Aminoglycosides-based Antibiotics Combination and Protective Isolation on Outcomes in Critically-ill Neutropenic Patients With Sepsis: (Combination-Lock01)
|
Phase 3 |