Australasian Anaesthesia 2011 - Australian and New Zealand ...

136 Australasian Anaesthesia 2011Intravenous Iron in Surgery and Obstetrics 137Iron Absorption and TransportAdults absorb about 1 mg per day of the 15 mg per day of dietary iron present in a normal adult diet. This is theapproximate amount that is lost daily by epithelial shedding in the digestive tract. Healthy individuals stay in ironbalance by increasing the fraction of iron absorbed from their diet if loss of iron increases (e.g. through blood lossin menstruating women). In iron deficiency, even with increased dietary intake, iron absorption rarely increases tomore than about 6 mg/day. Oral iron supplements will facilitate greater absorption rates than this.If blood loss continually exceeds the body’s ability to increase gastrointestinal iron absorption by a comparableamount, iron deficiency results. Thus, chronic blood loss, intestinal malabsorption, or dietary deficiency may allresult in iron deficiency. Both non-haem and haem iron are absorbed from the diet. Haem iron is better absorbedthan non-haem iron. Non-haem dietary iron in the form of ferric iron must first be reduced to ferrous iron by ferricreductase enzymes present in duodenal enterocytes, before it can be absorbed. Inhibition of gastric acid secretion,such as with proton pump inhibitors (PPI) or H2 antagonist use, will also impair the conversion of ferric iron to theferrous form. At this point, all absorbed dietary iron, will be present in the enterocyte as ferrous iron, bound to ferritinin the cell cytoplasm.The transfer of iron, (stored temporarily as ferritin), out of duodenal enterocytes onto transferrin in the plasmacannot take place without a membrane bound transport protein called ferroportin.This is the natural control point in intestinal iron absorption. Without ferroportin, iron remains trapped in theenterocytes. The short lifespan of enterocytes (2 days) ensures that iron trapped in this way is shed with thesenescent enterocytes into the faecal stream. The journey that dietary iron follows before being incorporated intoa new red blood cell involves one more protein: hepcidin. Hepcidin is the primary regulatory protein of iron absorptionand transport. It regulates iron absorption and transport by binding to ferroportin. In iron deficiency and in anaemia,hepcidin levels decrease, increasing available ferroportin. Iron absorption into the plasma increases and is ultimatelydelivered to the bone marrow or reticuloendothelial stores.Slow onset iron deficiencyIn chronic blood loss iron stores are usually depleted before anaemia develops. Severe chronic iron deficiency isaccompanied not only by anaemia, but also by deficiencies in a range of haem and non-haem iron dependentenzymes. Therefore, iron deficiency, if severe and prolonged, can cause dysfunction of iron-containing cellularenzymes and contribute to fatigue and loss of functional status via mechanisms independent of the anaemia itself.“Acute” iron deficiency (e.g. major surgical blood loss)Following major acute blood loss, because the majority of body iron resides in circulating haemoglobin, a patientmay develop an overall body iron deficit but retain normal iron stores at least initially. These iron stores howevermay be insufficient to allow complete replacement of the lost haemoglobin and the patient should be consideredto have an overall body iron deficit. This is best illustrated by an example:A hypothetical 80 kg male with a preoperative haemoglobin of 140 g/L undergoes a complicated bowel resectionfor colorectal cancer with an intraoperative blood loss of > 2.5 litres. Postoperatively he has a haemoglobin of75 g/L. He has lost approximately 1300mg of body iron intraoperatively (contained in the lost red cells). He will onlyhave body iron stores of 500 – 1000mg available to his bone marrow to manufacture new haemoglobin, which is300 – 800mg short of what he needs. He has just undergone major bowel surgery and his ability to replace theselosses through increased enteral absorption will also be limited. If he has a prolonged postoperative hospital stay,regular venesection for blood tests may result in ongoing iron losses, which may further exacerbate his problem.Anaemia of Chronic DiseaseMany diseases (e.g. chronic kidney disease, inflammatory bowel disease, malignancy) and some physiologicalstates (e.g. postoperatively) result in increased hepcidin levels. High levels of hepcidin bind the available ferroportinand induce its degradation. In the absence of adequate ferroportin, dietary iron is trapped in the enterocytes,preventing its transport into the plasma and delivery to the bone marrow for haemoglobin synthesis. Gastrointestinaliron absorption is inhibited and over time true iron deficiency may result.High hepcidin levels also inhibit the movement of iron from stores to the bone marrow, leading to a conditionknown as functional iron deficiency.Ferritin is also an acute phase reactant protein, which may be elevated in inflammatory states independent ofactual iron store status. In a patient with an inflammatory response, a clinician may, inappropriately interpret a raisedferritin, as indicative of adequate iron stores when in fact underlying true iron deficiency may be present.Menstruation and PregnancyIron deficiency is common in women of reproductive age due to the increased losses from menstruation, andincreased requirements during pregnancy. When pregnant the mother must increase her own red cell mass andprovide iron to her developing foetus. Iron deficiency and anaemia may be further compounded by any blood lossthat occurs during childbirth at the end of a pregnancy, a time when most mothers may have already depleted theiriron stores.• Pregnancy results in an overall additional iron requirement of around 1000mg. 3• IDA has been associated with low birth weight, prematurity, and maternal morbidity. 4• Menstruating women on average lose twice as much iron as men, and IDA is very common in women withmenorrhagia.Treatment points• Dietary iron alone (e.g. high red meat intake) is inadequate to treat established iron deficiency anaemia. 3• Common medications such as H2 antagonists or proton pump inhibitors decrease the effectiveness of oraliron therapy. 3• Gastrointestinal iron is poorly absorbed in patients with raised hepcidin levels (inflammatory disease,malignancy, immediate postoperative period)• Ferritin is an acute phase protein, which is often raised in patients with inflammatory disease processes andso may not accurately reflect body iron stores. Some anaemic patients, with high or normal ferritin, may stillhave true iron deficiency or functional iron deficiency, which will often respond to intravenous iron therapy.A useful algorithm for assessing anaemia in pre-operative patients has been developed by the Western AustraliaDepartment of Health Patient Blood Management Program a copy of which is provided at the end of this article.TREATMENT OPTIONS FOR ANAEMIAOral IronThe traditional first line treatment for iron deficiency anaemia (IDA) is oral iron therapy. In appropriate dosage andgiven enough time, oral iron is an effective treatment for simple iron deficiency anaemia. Some important considerationsin the anaemic perioperative surgical patient include:• Oral iron requires sufficient time to produce an adequate response. In IDA an increase of 20g/L every 3 weeksis the maximum to be expected. In practical terms this implies weeks to months of treatment.• 30 – 50% of patients may experience gastrointestinal adverse effects and non-compliance is high.• Oral iron will be ineffective in patients with raised hepcidin levels, (e.g. immediate postoperative period,chronic inflammatory disease)• H2-antagonists and proton pump inhibitor medications will reduce the efficacy of oral iron therapy.• It is important that patients take an oral preparation which contains an adequate dose of elemental ironwith100-200mg / day recommended (e.g. 1–2 Ferro grad). There are more than 100 iron containing over thecounter preparations available in Australia many of which contain woefully inadequate amounts of elementaliron (often < 5mg). Many would require 20 tablets for a therapeutic dose! 3Red Cell TransfusionThere is evidence that transfusion to correct iron deficiency anaemia is still an overused treatment. 5 Targeted useof transfusion is an appropriate strategy when severe anaemia compromises organ function (e.g. cardiac failure,angina pectoris) or there is ongoing serious bleeding. Iron therapy to fully replenish haemoglobin and iron storeswill still be required.Intramuscular IronIntramuscular injection of iron polymaltose is not recommended in most circumstances, 6 unless other approachesare impractical (e.g. in remote communities). It is painful, causes skin discolouration, repetitive injections are required,and it is less effective but no safer than IV administration.Intravenous IronPharmacology 7Administration of unbound inorganic ferric (Fe+3) iron in the early 1930s was observed to cause profound toxicity.Therefore all modern intravenous iron preparations are colloids consisting of a protective spheroidal carbohydrate,which encapsulates an inner iron hydroxide core. After IV injection the iron carbohydrates distribute in the plasma,from where the majority then enter the reticuloendothelial system (mainly liver, spleen and bone marrow). From hereiron is either stored as ferritin or transferred out via transferrin to the bone marrow to produce haemoglobin. A smallamount of “free iron” from the IV iron may be released directly onto transferrin in the plasma; this is more so withthe smaller molecules such as iron sucrose, which explains why it cannot be used for total dose infusions.Variation in the molecular weight of the encapsulating carbohydrate explains most of the differences in thepharmacological properties of the different preparations. The rate of clearance from the plasma and the rate ofrelease of iron from the ferric hydroxide core are inversely related to the total molecular weight. The general rule isthe smaller the molecule the more rapid the release of the iron, and the lower the maximum dose you can give.Adverse Effects and Toxicity 8Reactions During InfusionDuring administration of an intravenous iron polymaltose infusion a number of adverse effects can occur occasionally.The vast majority are not serious, are self-limiting in nature and have been described to varying degrees with allthe other intravenous iron preparations. These include nausea, rash, headache, mild hypotension, myalgia, arthralgia,chest and back pain. The mechanism of these adverse reactions is hypothesised to be related to the small amountof “free or labile” iron released during an infusion.