The Importance of Iron Administration in Correcting Anaemia after Major Surgery

World Health Organization (WHO) defines anaemia as a haemoglobin level under 13 g/dL in men and under 12 g/dL in women, affecting more than 30% of the worldwide population [1]. In surgical patients, preoperative anaemia has a prevalence of approximately 40% of patients, reaching 90% after major surgeries [2, 3, 4]. Iron deficiency anaemia (IDA) presents a high prevalence (affecting 1.2 billion people), and iron deficiency without anaemia (IDWA) being even more frequent [5, 6].

In case of significant blood volume loss, due to major surgery or prolonged hospitalisation [7], anaemia can develop or worsen, and it is usually associated with absolute or functional iron deficiency (the erythropoietic response is increased and outstrips the actual iron supply) [8, 9].

In normal conditions, the body contains about 3-5 grams of iron, almost 2 grams incorporated into haemoglobin and mature erythrocytes, and with each millilitre of lost blood, the body loses approximately 0.5 milligrams (mg) of iron [10, 11].

Over the last years, various studies have shown the negative impact of anaemia and iron deficiency in surgical patients, leading to increased red blood cells transfusion requirements, infections, slower recovery, ischemic complications (especially myocardial infarction), acute kidney injury [12], prolonged length of hospital stay, increased readmission, a more unsatisfactory perioperative outcome with increased mortality and morbidity [13, 14, 15]. Furthermore, acquired hospital anaemia, and in many cases, superimposed acquired iron deficiency, persists long after patients discharge, even beyond six months [16, 17, 18]. Therefore, correcting iron deficiency after surgery can help patients correct anaemia more rapidly, offering ‘the fuel’ for stress erythropoiesis (increasing iron bioavailability).

Various human and experimental studies have shown that iron deficiency is associated with dysregulations of glycaemia and lipids metabolism [19, 20] or that high glucose levels can lead to iron overload and increase oxidative stress [21]. In addition, iron deficiency, due to impairing the homeostasis of some mitochondrial enzymes, leads to inappropriate glycolysis with subsequent lactate accumulation [22].

The study aimed to determine the influence of intravenous iron administration in the postoperative period on improving haemoglobin correction trends. In addition, the influence of serum glycaemia and lactate on the haematological status of these patients was also evaluated.

After applying the inclusion and exclusion criteria, from the thirty patients to whom parenteral iron therapy was administered and was initially considered eligible, twenty-one remained in the study with a mean age (SD) of 58.90 (19.06) years, 38% being females and 62% males (Figure 2).

Fig. 2

Regarding the type of surgery, 52.58% were emergency surgeries, and 47.61% were elective. The mean duration for the surgical procedure in multiple trauma was 88 minutes.

Basic patients’ characteristics are presented in Table 1.

Haemoglobin values variation between postoperative, intraoperative and pre-iron administration times are presented in Figure 3.

Fig. 3

When anaemia and iron screening analyses were performed in the postoperative period (maximum 24 hours after surgery), iron deficiency was identified in all included patients (Table 2). The cut-offs used for iron deficiency were ferritin 100-300 μg/L along with transferrin saturation (TSAT) 20%, MVC < 92 fL, MCH < 33 g/dL, serum iron < 10 μmol/L and dTIBC > 36 μmol/L. Thirteen patients received 1000 mg and three patients 500 mg of ferric carboxymaltose in the first 48 hours after surgery, one patient 500 mg and one 1000 mg after 3-5 days and three patients received 1000 mg after seven days. The timing of iron administration differed according to patient status (renal function, inflammatory state). There were reported no adverse events related to iron administration.

Other bioumoral markers were analysed at 48 and 72 hours after an intervention to evaluate their influence on iron status in these patients. The absence of an acute inflammatory state was validated by the low levels of ferritin and fibrinogen (Table 2 and 3).

In studied patients, glucose value was correlated with haemoglobin correction trend at both analysed postoperative periods (p < 0.0001).

Thus, it appears that a high level of glycaemia slows the increase in haemoglobin value (Figure 4). No patient had diabetes nor was treated with insulin. This trend was not encountered for serum lactate, urea or creatinine.

Fig. 4

Using Quadratic statistical analysis, even though the mean haemoglobin level between iron administration and post-intervention measurements at 48 and 72 hours did not differ too much (8.51 g/dL versus 8.65 g/ dL and 8.84 g/dL), the trend analysis indicated p values < 0.0001 (Figure 5), meaning that the haemoglobin value is expected to rise over the next period. The multiple trauma patients (n = 5) developed acute kidney failure immediately postoperative, but statistical analysis showed that it does not influence the haemoglobin correction trend (p = 0.84).

Fig. 5

The causal relationship between the length of stay in the hospital and the haemoglobin was analysed, but no correlation was found (p = 0.55).

In addition, although the included patients presented substantial blood volume loss during the perioperative period, once intravenous iron therapy was initiated, none of the patients required transfusion.

The term “major surgery” is not standardised yet. However, it is known to include at least abdominal and thoracic surgery, which lasts more than thirty minutes, other extensive surgeries, including neurosurgery and coronary by-pass, significant blood loss (> 500 mL), intraoperative use of high vasopressors dose and long intraoperative time [24, 25]. Therefore, any patient undergoing major surgery is at risk of progressing to anaemia or iron deficiency and in need of haematological optimisation.

Postoperative anaemia and iron deficiency development have many determinants, including blood loss, blood sampling, preoperative anaemia, extensive surgery and inappropriate nutritional intake related to surgery, and it can appear at any age [26]. The patients in the present study presented either preoperative anaemia or significant intraoperative blood loss, and therefore they developed moderate to severe postoperative anaemia and were screened for iron deficiency. This aspect is more critical in the face of restrictive transfusion strategy (with haemoglobin thresholds depending on various comorbidities), as in our cases.

The importance of iron deficiency screening and treatment in surgical patients arise from the fact that maintaining an absolute iron deficiency may lead to iron deficiency anaemia or iron deficiency without anaemia and specific complications. On the other hand, intravenous iron administration for these patients prevents the appearance of iron-deficiency erythropoiesis [5, 27]. Additionally, acute kidney injury (AKI) is more often described in patients undergoing major surgical interventions due to different factors, including blood volume waste and iron deficiency. Furthermore, the literature regarding the impact of haemoglobin status and iron deficiency in patients with AKI is inconsistent, and most of the studies analysed the preoperative levels of these deficiencies [12].

Various studies have shown over the years that in the face of a ferritin level > 100 μg/L other markers may be used for iron deficiency screening and diagnosis. Thus, transferrin saturation, serum iron, MCV, MCH, mean corpuscular haemoglobin concentration (MCHC), dTIBC, reticulocyte haemoglobin content (CHr), red cell distribution width (RDW) are usually utilised, with soluble transferrin receptor (sTfR) or zinc protoporphyrins (ZPP) in the red cell not measured daily [27, 28, 29].

Considering that total daily iron absorption is less than 10 mg/day, the poorer postoperative gastric tolerance and altered gastrointestinal absorption in surgical patients, the use of oral supplements in the postoperative period is inefficient to correct iron deficiency [26, 30]. Various formulas can be used, including ferric carboxymaltose, ferric derisomaltose, iron sucrose, low molecular iron dextran or sodium ferric gluconate. The use of one of these agents is not standardised, being a choice made on availability, experience, patient’s allergies, and the available time to correct the iron deficit [31, 32].

Some researchers have shown a possible interconnection between iron and glucose metabolism. In healthy subjects, a high intake of glucose appears to increase hepcidin levels, leading to lower values of serum iron [33]. In our patients, high glucose levels were correlated with a decrease in haemoglobin correction trend, maybe due to the same mechanism. In patients with iron deficiency ± diabetes, high levels of glycated haemoglobin A1c were observed before treatment with iron, which corrected at normal values after the intervention [34, 35].

There are still controversies regarding postoperative iron administration. Most studies evaluate preoperative anaemia/iron deficiency screening and treatment. There are some studies about postoperative intravenous iron agents’ use with good outcomes regarding haemoglobin and iron status at 4-weeks follow-up in major elective surgery [36], improved haemoglobin level at two weeks after major orthopaedic surgery [37]. In contrast, some reports found that postoperative iron administration does not significantly correct haemoglobin level or influence the transfusion rate [38]. Therefore, research is needed to clarify the benefits of using postoperative intravenous iron.

At the postoperative screening, all included patients with mean values of intraoperative bleedings more than half a litre presented absolute iron deficiency. Our patients, who received intravenous iron treatment with ferric carboxymaltose, showed a favourable haemoglobin correction trend. Extending the number of patients and the follow-up period will allow us to test our primary hypothesis.