Changes in Hepcidin Levels in an Animal Model of Anemia of Chronic Inflammation: Mechanistic Insights Related to Iron Supplementation and Hepcidin Regulation

We examined changes in hepcidin (closely associated with anemia of chronic inflammation (ACI)) and upstream regulatory pathways after intravenous (IV) iron supplementation in an ACI animal model. ACI was induced in male Sprague-Dawley rats by intraperitoneally administering complete Freund’s adjuvant (CFA). Two weeks after starting CFA treatment, ACI rats received IV iron (CFA-iron) or vehicle (CFA-saline). Three days after IV iron treatment, iron profiles, hepcidin levels, and expression of proteins involved in the signaling pathways upstream of hepcidin transcription in the liver were measured. In CFA-treated rats, anemia with a concomitant increase in the levels of serum inflammatory cytokines and reactive oxygen species occurred. In CFA-iron rats, hemoglobin (Hb) concentration was still lower than that in control rats. In CFA-saline rats, hepatic hepcidin and ferritin levels increased compared with those in control rats and were further increased in CFA-iron rats. In CFA-saline rats, NADPH oxidase- (NOX-) 2, NOX-4, and superoxide dismutase levels in the liver were upregulated compared with those in control rats and their levels were further increased in CFA-iron rats. In CFA-saline rats, activities of the IL-6/STAT and BMP/SMAD pathways were enhanced in the liver compared with those in control rats and their levels were further increased in CFA-iron rats, whereas IL-6 expression remained unaffected after IV iron administration. In HepG2 cells, iron caused phosphorylation of STAT-3 and SMAD1/5 and knockdown of STAT-3 and SMAD1/5 using siRNAs reduced iron-induced hepcidin upregulation to levels similar to those in corresponding control cells. Renal erythropoietin expression and serum erythroferrone concentration were lower in CFA-iron rats than those in control rats. In ACI rats, IV iron supplementation did not recover Hb within three days despite an increase in hepatic ferritin levels, which might be attributable to an additional increase in hepcidin levels that was already upregulated under ACI conditions. Both STAT-3 phosphorylation and SMAD1/5 phosphorylation were associated with hepcidin upregulation after IV iron treatment, and this seems to be linked to iron-induced oxidative stress.

Organizational Strategies for the Management of Intravenous Iron Therapy in Non-Hospitalized Settings: A Safe Opportunity to Implement Patient Blood Management in Italy

This article analyzes the recommendations issued by the Emilia Romagna region in July 2020 on “Organizational strategies for the safe management of intravenous iron therapy in patients in non-hospitalized settings”. The objective of these recommendations is to set up safe intravenous iron administration sites outside the hospital environment across the national territory. The document facilitates the organization of methods for intravenous iron infusion that are safe for the patient and correct from a medico-legal perspective. In addition, it opens the way for the widespread use of iron infusion in the field, providing benefits to patient quality of life. This program prevents unnecessary transfusions, reduces costs, prevents overcrowding in hospitals in the event of a pandemic, and enables patient treatment in the field, thus, saving on the use of personnel.

The Ideal Time for Iron Administration in Anemia Secondary to Blood Loss—An Experimental Animal Model

Background: Anemia and iron deficiency are two of the main public health problems worldwide, associated with negative outcomes in surgical patients. This experimental study aimed to create a model of acute iron deficiency with anemia through blood loss and extensive surgery. Afterwards, intravenous iron was administered to correct the iron deficiency and to improve the hematological parameters in distinct moments regarding the surgical time. To assess the optimum time for therapeutic intervention, experimental subjects were compared, performing clinical, paraclinical, and histological examinations, as well. Methods: Male rats (n = 35), aged 11–13 months, were randomly designated into six groups. Anemia and iron deficiency were obtained through a 15% blood volume loss, followed by major surgical intervention (femur fracture and osteosynthesis using Kirschner wire). Therapeutic intervention was obtained with an intravenous ferric carboxymaltose infusion, as follows: group II: intraoperative (n = 7), group III: 48 h after surgery (n = 7), group IV: 48 h before surgery (n = 5), and group V: seven days before surgery (n = 6). Group I (n = 5) was left anemic, while group 0 (n = 5) was nonanemic without therapeutic intervention. Results and Discussion: In group I, serum iron lower than in group 0 (27.04 ± 6.92 μg/dL versus 60.5 ± 2.34 μg/dL), as well as hemoglobin (10.4 ± 0.54 g/dL versus 14.32 ± 2.01 g/dL) and ferritin values (22.52 ± 0.53 ng/mL versus 29.86 ± 3.97 ng/mL), validated the experimental model. Regarding wound healing after surgical trauma, we observed that neovascularization was more significant in group III, followed by group V, with fewer neutrophils, a well-represented and rich in lymphomonocytes inflammatory infiltrate associated with the biggest collagen fiber dimensions. The periosteal reaction and callus area presented thicker trabeculae in groups II and III compared to the anemic group. Conclusions: This original experimental study assessed the effect of perioperative intravenous iron administration at a specific time by comparing the weight, hematological, and iron status-defining parameters, as well as histological characteristics of the included subjects. The present findings highlight that correcting the iron deficiency in emergency settings through intravenous iron administration intraoperatively or 48 h postoperatively could determine the improved bioumoral parameters, as well as a better evolution of the postoperative wound and bone healing compared to the anemic group or subjects that received therapeutic intervention 48 h before surgery.

The Importance of Iron Administration in Correcting Anaemia after Major Surgery

Introduction: Postoperative anaemia can affect more than 90% of patients undergoing major surgeries. Patients develop an absolute iron deficiency in the face of significant blood loss or preoperative anaemia and major surgery. Studies have shown the negative impact of these factors on transfusion requirements, infections, increased hospitalisation and long-term morbidities. Aim of the study: The research was performed to determine the correlation between intravenous iron administration in the postoperative period and improved haemoglobin correction trend. Material and methods: A prospective study was conducted to screen and treat iron deficiency in patients undergoing major surgery associated with significant bleeding. For iron deficiency anaemia screening, in the postoperative period, the following bioumoral parameters were assessed: haemoglobin, serum iron, transferrin saturation (TSAT), and ferritin, direct serum total iron-binding capacity (dTIBC), mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH). In addition, serum glucose, fibrinogen, urea, creatinine and lactate values were also collected. Results: Twenty-one patients undergoing major surgeries (52,38% were emergency and 47,61% elective interventions) were included in the study. Iron deficiency, as defined by ferritin 100-300 μg/L along with transferrin saturation (TSAT) < 20 %, mean corpuscular volume (MVC) < 92 fL, mean corpuscular haemoglobin (MCH) < 33 g/dL, serum iron < 10 μmol/L and direct serum total iron-binding capacity (dTIBC) > 36 μmol/L, was identified in all cases. To correct the deficit and optimise the haematological status, all patients received intravenous ferric carboxymaltose (500-1000 mg, single dose). Using Quadratic statistical analysis, the trend of haemoglobin correction was found to be a favourable one. Conclusion: The administration of intravenous ferric carboxymaltose in the postoperative period showed the beneficial effect of this type of intervention on the haemoglobin correction trend in these groups of patients.

Maternal iron deficiency perturbs embryonic cardiovascular development in mice

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene–environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.

Preoperative Sucrosomial Iron Supplementation Increases Haemoglobin and Reduces Transfusion Requirements in Elective Heart Surgery Patients: A Prospective Randomized Study

Background: Low preoperative haemoglobin is frequently observed in heart surgery patients and is associated with a significant decrease in haemoglobin between post-operative days 2 and 3, known as haemoglobin drift. Overall, these patients tend to receive many RBC transfusions. Since iron homeostasis is often impaired in these patients, restoration of iron availability might override iron-restricted erythropoiesis. However, reduced tolerance to oral iron salts has limited this strategy to intravenous iron administration. Study Design and Methods: The purpose of this study was to assess whether preoperative supplementation with oral sucrosomial iron, a new iron-delivery technology with improved tolerance and bioavailability, might be an effective strategy for this patient population. One thousand consecutive patients were randomized and received either a one-month course of sucrosomial iron (60 mg/day) or no treatment prior to elective heart surgery at a single high-volume centre (ClinicalTrials.gov NCT03560687). Primary end-points were haemoglobin concentration on the day of hospital admittance and number of blood transfusions. Secondary end-points were haemoglobin drift, tolerance of treatment and cost-effectiveness of sucrosomial iron administration. Results: Baseline haemoglobin in the treatment group was higher (by 0.67 g/dL; p<0.001) than that in the control group. The percentage of patients in the treatment group who required transfusion (35.4%) was half that in the control group (64.6%). The average number of transfused units per operation was 0.95 vs. 2.03 in the treatment and control groups, respectively. Haemoglobin drift was substantially similar in the two groups, and the tolerability of treatment was excellent (98%). The overall cost of treatment was 156 Euros less in the treatment group, expressed as a raw cost of transfusion. Conclusion: In elective heart surgery, routine preoperative sucrosomial iron administration seems to be a safe, well-tolerated and cost-effective strategy to increase preoperative haemoglobin and reduce the need for allogeneic blood transfusions.

Positive Human Contact and Housing Systems Impact the Responses of Piglets to Various Stressors

This experiment studied the effects of lactation housing systems and human interaction on piglets’ responses to routine stressors. Forty litters of piglets were reared in either a standard farrowing crate (FC) or a loose farrowing and lactation pen (LP; PigSAFE pen) and received either routine contact with humans (C) or regular opportunities for positive human contact (+HC; 3 min of patting, stroking and scratching 5 times/week). Behavioural and physiological responses to routine husbandry procedures, weaning, novelty and humans were studied in addition to effects on piglet growth, injuries and survival. Compared to C piglets, +HC piglets vocalised for shorter durations (p = 0.018) during husbandry procedures and showed a lower intensity of escape behaviour during iron injection (p = 0.042) and oral vaccination (p = 0.026) at 3 d of age, capture at 2 wk of age (p < 0.001), and intramuscular vaccination (p = 0.005) at 3 wk of age. +HC piglets at 2 wk of age were faster than C piglets to approach (p = 0.048) and interact (p = 0.042) with a stationary unfamiliar human. Compared to LP piglets, FC piglets showed a lower intensity of escape behaviour during capture and iron administration by a stockperson at 3 d of age (p = 0.043). FC piglets at 2 wk of age were faster than LP piglets to approach (p = 0.005) and interact (p = 0.027) with a novel object and approach (p = 0.009) and interact (p = 0.008) with an unfamiliar human. FC piglets had fewer injuries than LP piglets at 2 wk of age (p = 0.004). +HC pigs had fewer injuries than C pigs after weaning (p = 0.003). After weaning there were more pigs from LP than FC observed to be upright (both stationary, p = 0.002 and walking, p = 0.024), vocalizing (p = 0.004), nosing another pig (p = 0.035) and nosing the pen floor (p = 0.038). There were no significant effects on neutrophil:lymphocyte ratios or plasma cortisol concentrations 1.5 h after weaning. However, 25 h after weaning +HC pigs had higher haptoglobin concentrations than C pigs (p = 0.002), and C/LP pigs had higher cortisol concentrations than +HC/LP and C/FC pigs (p = 0.012). There were no significant effects on piglet growth, the number of piglets born alive or the number stillborn, however there were more piglets weaned from FC than LP (p = 0.035). The results from this experiment raise questions that require further research on the ability of pigs reared in loose pens to cope with stressors such as exposure to humans, novelty, husbandry procedures and weaning. This experiment also provides evidence that regular positive human interaction reduces pigs’ fear of humans and husbandry procedures imposed by stockpeople. More research is required to determine if any of these effects are sustained long-term.