A stain on iron therapy (2024)

Iron staining is an unwanted and in some casespermanent adverse effect of intravenous ironadministration. Cosmetically unacceptable stainingmay cause distress and have psychologicalimplications for the patient.

There should be a suitable indication for parenteraliron therapy. Patients must be advised of the riskof harm and give their informed consent beforereceiving parenteral iron.

Strategies to minimise the risks of staining withintravenous iron include appropriate cannulation andclose monitoring of the infusion. Stop the infusionif there are signs of extravasation.

Laser therapy may be a treatment option in cases ofpersistent discolouration due to iron staining.

Iron deficiency is a common condition and a largecontributor to anaemia.1 The prevalence ofiron deficiency anaemia is high in younger women andindigenous Australians.2 Treatment options tocorrect iron deficiency in Australia include oraland parenteral iron.3Within the last decade the use of intravenous ironhas been increasing,4particularly in the community. This is because ofnewer iron salts with favourable adverse effectprofiles and shorter infusion times for intravenousformulations. These include ferric carboxymaltoseand ferric derisomaltose. For patients in hospital,iron polymaltose or iron sucrose can also be used.

An uncommon adverse effect of parenteral iron is skinstaining (see Fig.). This is not anew phenomenon as it is a well-known adverse effectof intramuscular iron.5Iron staining can occur with intravenous infusionsif there is extravasation into the surroundingtissue. The use of intramuscular ironadministrationis limited in practice,3 but the injectioncan be given into an unexposed site. However,administration at an unexposed site is notnecessarily possible when giving iron intravenously.A rise in reports of iron staining6-10 may correspondwith the increasing use of intravenous iron inclinical practice.6-13

Fig. - Iron stain

The rate of skin discolouration with intravenous ironpreparations has been reported in clinical trials as0.68%14 to 1.3%.15 Postmarketingreports suggest the incidence may be lower and skinnecrosis has not been reported. However, ironstaining may be under-reported to pharmacovigilancedatabases. A review of the French pharmacovigilancedatabase from 2000 to 2016 found only 51 cases ofcutaneous pigmentation with iron.¹²

Postmarketing reports to the Therapeutic GoodsAdministration (TGA) Database of Adverse EventNotifications,¹⁶ fromMarch 2014 to October 2019, included 27 cases forferric carboxymaltose. Thesereports includedthe terms skin discolouration or hyperpigmentation,haemosiderin stain, pigmentation disorder,infusion/injection/administration sitediscolouration, or extravasation. The TGA datainclude eight cases of pigmentation disorder or skindiscolouration with iron polymaltose, with the firstreport in 2005. There are currently no reports forferric derisomaltose, but this adverse effect isincluded in the product information.

Is parenteral iron indicated?

Once iron deficiency is diagnosed, establish thecause. The decision on appropriate treatment shouldthen consider the patient’s treatment goals. Thisincludes assessing the options for correcting theiron deficiency and their potential adverse effects.Dietary intake, oral supplements or parenteral ironare suitable options.³

Parenteral iron is usually only indicated when oraliron therapy has failed.3 However, there aresome patient cohorts who may benefit fromintravenous iron without a trial of oral therapy.They include patients who have heart failure with areduced ejection fraction,15 those undergoinghaemodialysis,17 andpregnant women in their second or third trimesterrequiring rapid iron replenishment.¹⁸

Inform patients about skin staining

Although the incidence of iron staining appears to berelatively low, its potential irreversibility andthe cosmetic impact it may have warrant discussionwith patients. The Medical Board of Australia hasreminded medical practitioners to advise patientsabout the risk so that they can give informedconsent to treatment.19 Using a patientinformation brochure about iron staining may assistwith this. The BloodSafe organisation has a usefulleaflet available in English and other languages.20 When intravenousiron is indicated and patients choose to receive aninfusion, it is advisable to document the contentand outcome of the discussion about risks includingdiscolouration or staining.

Correct injection site and infusion technique

The infusion sites used for intravenous therapy mayinfluence the rate of extravasation due to thepotential for vessel damage related to movement ofthe cannula.^21,22 Administration ofintravenous iron via cannulation at sites of flexion(e.g. antecubital fossa, wrist) or on the back ofthe hand should be avoided when possible. If thesesites must be used, the smallest suitable cannulasize may reduce the likelihood of vessel trauma.22 Try to minimisecatheter movement by securing the cannula21-23 and usinganextension set.24 When using smallergauge devices, it may be necessary to slow theinfusion to minimise the risk ofdislodgement.²⁵

The number of attempts at cannulation should beminimised as there is an increased risk ofextravasation due to multiple venouspunctures.^21,22 For patients whoare difficult to cannulate, seek the expertise ofmore experienced staff. Although postponingintravenous iron therapy may inconvenience thepatient, it is unlikely to result in adverseclinical outcomes. Intravenous iron infusion israrely urgent.

The patency of the cannula should be checked bygiving 5–10 mL of sodium chloride 0.9% before theinfusion.21

Monitor for extravasation

The review of cutaneous pigmentation reported to theFrench pharmacovigilance database suggestedimprovements in monitoring are necessary to detectextravasation.12Patients who experience iron extravasation resultingin staining may describe pain, swelling, andfeelings of pressure or pricking at the infusionsite.13 Patientsshould therefore be told to notify staff of any ofthese symptoms (Box 3). This is animportant consideration for patients who do notunderstand English. Administration of intravenousiron must be avoided if the patient’s ability toreport these symptoms is reduced (e.g. anaesthetisedpatients). Early cessation of the infusion may limitthe amount of solution that enters the tissues andcould minimise the extent of staining.

Close assessment of the cannula site during infusionis essential to enable early identification ofextravasation. The site should never be covered upwith a bandage. Observations of the cannula siteshould be timed to correspond with monitoring of thepatient’s othervital signs in accordance withlocal protocols for infusions.26 Giving intravenousiron infusions overnight must be avoided as it ismore difficult to observe extravasation and stainingin the dark.

Staff training

In order to ensure the best outcomes for patients,health professionals involved with the prescribing,administration and monitoring of intravenous ironmust be adequately trained and competent. A setprotocol that outlines best practice for intravenousiron administration, including cannulation, shouldbe followed. Staff must be aware of the monitoringrequirements and the symptoms of potential adverseeffects.

There are limited options to reverse iron staining.Topical therapies, lymphatic drainage and massageshave been tried without success.^9,13The most evidence for successful reversal of ironstaining is with laser therapy.

One review assessed 29 patients who had reportedaccidental staining from iron infusions over anine-year period.13Thirteen patients had laser therapyand eightcompleted treatment. Regression of iron stainingtook an average of 5.6 laser sessions over one totwo years. The type of laser is important with mostevidence being for quality-switched Nd:YAG orpicosecond. The patient’s individual skin type mayalso influence the success of laser treatment. Ingeneral, laser therapy was well tolerated.

Laser therapy is available in Australia, but theremay be significant financial barriers as repeatedapplications are required. If the patient isconcerned about the staining, early referral to adermatologist with a laser clinic specialising inquality-switched Nd:YAG and picosecond laser isappropriate.

There should be a clear indication for usingintravenous iron. Patients need to give informedconsent for the infusion.

Iron extravasation can be cosmetically unacceptablefor patients so strategies should be put in place toprevent it from occurring. These include appropriatevein selection, securing the cannula and closemonitoring during the infusion. In addition, thepatient should be advised to report any pain,irritation or swelling at the infusion site.

In the event of extravasation and persistentstaining, repeated laser sessions over one to twoyears may be required. However, iron staining can bepermanent.

Conflict of interest: none declared

Acknowledgment: A thank you is extendedto Carmela Corallo,Formulary Manager atAlfred Health, for hertranslationskillsand review of thismanuscript and Jana Waldmann, Librarian, ThePrince Charles Hospital Library, who assisted byperforming a literature search.