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URGENT CARE Special Section

Ferrous Sulfate Urgent Care Section Urgent Care

100 Tablets

Recognizing and Managing

Christian Balmadrid, MD Since urgent care physicians will encounter patients Senior Emergency Resident suffering from excess iron intake only occasionally, iron toxicity can be challenging when it does present. The Michael Bono, MD Professor of Emergency Medicine authors review the basic science and the signs, symptoms and course of illness and provide an update on the clinical Eastern Virginia Medical School Norfolk, Virginia management of these patients. © 2009 Punchstock 36 EMERGENCY MEDICINE | MAY 2009 www.emedmag.com Urgent Care Section 37

<< IRON TOXICITY TOXICITY IRON TRACK

4 Overdoses 4

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In children, are usually the result of ingestion of adult formulations, especially prenatal vitamins. >> MAY 2009 MAY While 2 Common Iron Preparations Common

and the elemental iron content of someand the elemental iron content of 4 Data extracted from: Velez LI and Delaney KA. Data extracted from: Velez Compound Elemental iron 1. TABLE Elemental Compound ferrous sulfate ferrous fumarate ferrous gluconate ferric pyrophosphate 14% ferrocholinate ferroglycine sulfate ferrous sulfate, dried 20% 33% ferrous carbonate, anhydrous 12% 30% carbonyl iron 38% 16% 33% 100% The toxicity of iron depends on the amount ofThe toxicity of iron depends on the popular and prenatal vitamin formu- lations on the market is 2. shown in Table of iron, however, can quickly lead to of iron, however, in thesaturation, resulting in free iron circulating serum, which is directly toxic to organs. contains.elemental iron the ingested formulation are listed inSome common iron preparations 1 Table COURSE OF ILLNESS Iron has two distinct toxic effects. First, it is di- rectly caustic to the GI mucosa, leading to vom- the minimum toxic and the of iron are not firmly established, it can be expected that in- gestion of less than 20 mg/kg of elemental iron will usually cause no symptoms, 20 to 40 mg/kg will 40 to 60 mg/kg will provoke produce mild toxicity, moderate symptoms, and levels greater than 60 mg/kg can lead to severe toxicity. an essential cofactor in the normal function of he- an essential cofactor in the normal function and numer- moglobin, myoglobin, cytochromes, throughous other catalytic enzymes. It is absorbed in thethe digestive tract, then bound to transferrin 15% to 35% of transfer- bloodstream. Normally, iron binding capacity is utilized. rin’s

1 1 , but the Although 1 In children, 2 3 Physicians’ Desk Reference cute care settings form the first line settings form the cute care un- against the relatively of defense from problem of toxicity common specifically from heavy and This article will review the basic science, the This article will review Iron is an essential , meaning it is an ele-

More than 100 iron-containing preparations areMore than 100 iron-containing preparations listed in the younger thanUnintentional ingestions by children cases,6 years accounted for 83% of those reported while intentional overdoses (suicide attempts) were much more common in adults. vast majority of cases in 2004 were, as usual, avast majority of cases in 2004 were, ingestions. result of iron-containing multivitamin intentional overdose accounted for only a small fraction of the cases, it accounted for the majority of the admissions (58%), and resulted in a much higher mortality rate (10% vs 1%). pediatric multivitamin formulations are usually minimally toxic, and life-threatening poisonings are usually the result of ingestion of more potent adult formulations, especially prenatal vitamins, which have the highest iron content. In one case the birth of a sibling within 6 months control study, was identified as a risk factor for iron ingestion in children less than 3 years old.

CAUSES AND PATTERNS CAUSES AND PATTERNS OF IRON TOXICITY by theReports of iron exposure collected CentersAmerican Association of Control in 2004. (AAPCC) totaled approximately 35,000 A identifying signs and symptoms, and the prin- identifying signs applicable to pa- ciples of clinical management hope our We iron toxicity. tients suffering from prepared discussion will help you to be optimally low in- to provide their care, but the relatively make these cidence of the diagnosis tends to recom- cases challenging by nature. It is strongly poison mended that a toxicologist or the regional for suspected control center always be consulted from iron or any other metal. iron. If this illness presents to an urgent care iron. If this illness not maintained familiarity physician who has treatment, the potential for with its effects and due to misdiagnosis or morbidity and mortality is significant. inappropriate treatment ment that the body needs but does not produce and must extract from dietary sources. It acts as www.emedmag.com Urgent Care Section 38

IRON TOXICITY

EMERGENCY MEDICINE toxicity usually will not progress beyond Stage 1, toxicity usually willnotprogressbeyond Stage1, povolemic shock.Patients with mildtomoderate occurs inthisstage,itisusually secondarytohy- results willshowametabolic acidosis.Ifdeath arrhea, hematemesis,melena, andlethargy. Lab Other symptomscaninclude abdominalpain,di- is themostsensitiveindicatorofseveretoxicity. 6 hourswithenteric-coatedirontablets. toxicity, butmaybe delayedupto following theingestioninsevere cur withinthefirst1to1.5hours mucosa. Vomiting willusuallyoc- iron’s directtoxiceffectsontheGI by GIeffects,andistheresultof Stage 1ischaracterizedprimarily fects, 30minutesto6hours ated withlargeringestions. toms, butitmaybequiteacceler- classical timelineforthesesymp- As notedforeachbelow, there isa symptoms mayoverlap,however. in fourorfivestages.Signsand iron toxicityistypicallydescribed toxic tothemyocardium. illary permeability, andisdirectly rect vasodilator, canincreasecap- cellular level,ironalsoactsasadi- shock inseverecases. vomiting anddiarrhea,canleadto GI fluidlossesthatoccurfromthe effects, inadditiontothesevere of oxidativephosphorylation. in theKrebscycle,anduncoupling inhibition ofenzymaticprocesses lipid membraneofmitochondria, which resultsfromalterationofthe adenosine triphosphatesynthesis, tant consequencesisimpairmentof formation. Oneofitsmostimpor- lipid peroxidationandfreeradical metabolism, primarilythrough tis. Second,itimpairsintracellular bleeding, perforation,andperitoni- sult inhemorrhagicnecrosiswith pain. Inseverecases,itcanre- iting, ,andabdominal Stage 1:Gastrointestinalef- Depending onthesource,acute In additiontoitseffectsatthe

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MAY 2009 4 2 These These 2,4 .

Multivitamin Formulations Sunkist Flintstones WmnSadr iePecito 10mg 5mg 5mg 10mg 5mg One-A-Day Women/Standard LifePrescription Women/Basic LifePrescription 10mg/mL Men/BasicLifePrescription 12mg Natural MD Complete forWomen Complete forMen Centrum 18mg Shamu andHisCrew Drops 18mg 60mg Tablet Poly-Vi-Sol With Iron Centrum KidsCompleteRugrats Centrum Jr. PlusIron Bugs BunnyWithIron 29mg CHILDREN’S Natalins 45 Natalins Rx NataChew PrenatalVitamins PRENATAL VITAMINS Preparation Elemental TABLE 2. mg iron Stresstabs One-A-Day Centrum ADULT MULTIVITAMINS Data extractedfrom:LiebeltLLandKronfolR. ® Cmlt 18mg Complete ® ® Sle 4mg Silver 18 mg ®

® ® ® Elemental IronContentofSelect Pu rn 18mg PlusIron Wt rn 18mg WithIron Wmns 27mg 18mg Women’s Maximum GI symptoms haveresolvedbecausethe circulat- period ofapparentrecovery inwhichthepatient’s may havedelayedeffects). enteric coatedirontablets wereingested,which any serioussideeffectswill occur(again,unless after apresumedironingestion,itisunlikelythat and ifapatientremainsasymptomaticfor6hours Stage 2:Latentphase,6to 24hours ® Pu rn 18mg PlusIron ® 18 mg 2 2,4 www.emedmag.com . This is a Thisisa

Urgent Care Section 39

IRON TOXICITY IRON ; Velez LI and ; Velez 2 EMERGENCY MEDICINE

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moderate (rarely develop moderate (rarely develop serious complications) severe (serious systemic toxicity) and significant morbidity mortality

MAY 2009 MAY Peak Serum Iron in Serum Iron Peak

4 Delaney KA. Data extacted from: Liebelt LL and Kronfol R TABLE 3. TABLE Peak serum iron (μg/dL) none 50-150 Toxicity mild 150-300 300-500 >500 >1000 Correlation with Toxicity with Correlation from Stage 1 may recur within the first few hours, from Stage 1 may recur within the first hypovole- resulting in further hypovolemia and distributive shock mic shock. A few hours later, effect as a vasodi- may occur secondary to iron’s perme- lator and its tendency to increase vascular direct toxicity to of concern is iron’s Also ability. 2,4 Additionally, Additionally, 2 2 Patients will have severe metabolic aci- Patients will have severe metabolic . Different types of shock may occur in this Different types of shock may occur Stage 3: Shock and , 6 toStage 3: Shock and metabolic acidosis,

dosis in this stage, partly as a result of hydrationdosis in this stage, partly as a result hydrogenof absorbed ferric , which releases ions as a by-product of the reaction. stage, including hypovolemic, distributive, and stage, including hypovolemic, distributive, symptoms . Gastrointestinal 72 hours lactic acidosis results secondary to hypovolemialactic acidosis results secondary to iron-inducedand poor tissue perfusion as well as mitochondrial dysfunction. ing free iron has redistributed into the reticuloen- has redistributed ing free iron itsno longer produces system, where it dothelial stage may this In severe toxicity, toxic GI effects. is to dis- challenge, clinically, not occur at all. The the patient in a true latent phasetinguish between to more serious stages and thethat may progress mild GI toxicity that has nowpatient who only had examination and assessmentresolved. Careful Although patients in the latentmay produce clues. stable, they are not necessarilyphase may appear may still be poor perfusion,asymptomatic. There to metabolic acidosis),hyperventilation (secondary to hypovolemia). or oliguria (secondary www.emedmag.com Urgent Care Section 40

IRON TOXICITY

>> EMERGENCY MEDICINE often befatal. but ifitdoesoccurwill after ironingestionisrare, Fulminant hepaticfailure FAST obstruction. the GImucosaheals,scarringcanresultinbowel within 4hoursafterasevereironoverdose. to 96hours. effect andprognosisispoor. has reachedthemitochondria,therapylittle chondrial injury. Onceacriticalamountofiron dysfunction, whichisprimarilyaresultofmito- sis). Deathmayoccurfromwidespreadcellular toxicity, ,andmetabolicacido- adult respiratorydistresssyndrome(fromdirect dice, ,andworseningcoagulopathy), renal andhepaticdysfunction(leadingtojaun- agulopathy (ironcausesthrombindysfunction), hemorrhage, bowelperforation,iron-inducedco- occur itwilloftenbefatal. failure afterironingestionisrare,butifitdoes effects onenzymaticreactions.Fulminanthepatic at higherrisktobedamagedbyiron’s disruptive cytes haveahighmetabolicactivityputtingthem late throughtheportalcirculation.Also,hepato- cause ofthehighironconcentrationsthatcircu- isparticularlyvulnerabletoirontoxicitybe- common causeofdeathfromironpoisoning. probability of excessive cal examisrequiredinthese patientstogaugethe pain aresononspecific.Agood historyandphysi- symptoms ofnausea,vomiting, andabdominal a highindexofsuspicion because itspresenting witnesses toaningestion, thediagnosisrequires tient beingfoundunresponsiveorachildwithno that informationisunavailable,asincasesofapa- ingested iron,eitherwithsuicidalintentorac- Patients willoftenpresentknowingthatthey Iron poisoningisprimarilyaclinicaldiagnosis. CLINICAL ASSESSMENT shock within1to2days. the myocardium,whichmayleadtocardiogenic Stage 5:Bowelobstruction,2to8weeks. Stage 4:/hepaticnecrosis,12 Other symptomsatthisstagemayincludeGI

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Fulminant hepaticfailurecanoccur

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MAY 2009 << iron 2 5 the ingestion. When the ingestion.When timing andquantityof iron ingested,andthe motivation, typeof It isessentialtoprobe the caseinchildren). cidentally (asisoften Itisthesecondmost 2 exposure. 2 The

2 As As els. which TIBCwasgreaterthantheserumironlev- have beendocumentedcasesofirontoxicityin are receivingdeferoxaminetherapy. Also,there can oftenbeinaccurate,especiallyifpatients clinically supported,asmeasurementsofTIBC fects. Unfortunately, thistheoryhasnotbeen be nofreeironcirculatingtocauseitstoxicef- is higherthantheserumironlevels,thereshould iron boundtotransferrin.Theoretically, ifTIBC pacity (TIBC),whichmeasurestheamountof little ornovalue,suchastotalironbindingca- ordered are: shown inTable 3. serum ironlevelsusuallycorrelatewithtoxicityas acute irontoxicityistheserumlevel.Peak hours pastingestionmaybedeceptivelylow. lularly, soconcentrationsmeasuredmorethan8 cleared fromtheserumandenterstissuesintracel- free ironcirculatingintheblood.Ironisrapidly ever, thatmeasurementsofserumironlevelreflect a verysensitive test. graphically visibleatall,so x-rayimagingisnot able andliquidformulations willnotberadio- and contentofelemental iron, andmostchew- of irontabletsdependson the typeofformulation confirm thediagnosis.However, theradiopacity presence ofirontabletsintheGItract,whichcan into thetissues. tively lowafteringestedironhasredistributed tioned problemofserumironbecomingdecep- Certain additionalassessmentsmaybeof • typeandcrossmatch. • • • • • The otherlaboratorystudiesthatshouldbe The mostusefullaboratoryvalue Plain radiographscansometimesrevealthe 2 and tosis isanonspecificmarkerofirontoxicity); complete bloodcountw/differential(leukocy- to assesshepaticfunction; prothrombin time/partialthromboplastintime patic function; aminotransferases andbilirubintoassesshe- hyperglycemia, andassessfluidstatus; abnormalities, aniongapmetabolicacidosis, basic metabolicpaneltocheckforelectrolyte of acidosis; verely poisonedpatientstocheckfordegree arterial bloodgasesinmoderatelytose- Thesecaseslikelyillustratetheabove-men- 2,4 Itisimportanttonote,how- 5 www.emedmag.com to follow in follow in 4 Urgent Care Section 41

<< . IRON TOXICITY IRON QQ TRACK

. 2005;23(5):589- . 1989;7(5):459-463. EMERGENCY MEDICINE . 2000;30(3):71-90.

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If an asymptomatic patient If an asymptomatic than has ingested less 20 mg/kg of elemental iron according to the observation is history, sufficient and discharge is appropriate if there is no change in the patient’s condition after 6 hours. Am J Emerg Med >> Am J Emerg Med

MAY 2009 MAY 2 Curr Probl Pediatr . 1st ed. Philadelphia, Pennsylvania: WB For those not in shock, how- For those 7 2 . 2003;168(12):1539-1542. Clinical of the American Association of Poison Control Centers toxic of the American Association of Poison Control Centers toxic exposure surveillance system. 666. http://www.uptodateonline.com/patients/content/topic.do?topi Updated September 8, 2008. Accessed cKey=~a8nJ1gFQ5I2CT. April 20, 2009. soning in young children: association with the birth of a sibling. CMAJ RM, et al., eds. In: Marx JA, Hockberger RS, Wallas mercury. Concepts and Clinical Practice Emergency Medicine Rosen’s 6th ed. Philadelphia, Pennsylvania: Mosby; 2006: 2418-2451. of abdominal radiographs in visualizing chewable iron supple- ments following overdose. Saunders; 2001: 305. eds. The correct duration of therapy The correct duration There is no role for gastric lavage, activatedThere is no role for gastric lavage, is typically recommended over the intramuscular over the intramuscular recommended is typically for those in particularly severe toxicity, route in shock. circulatory ever, the FDA recommends administering defer- the FDA recommends ever, oxamine intramuscularly. effi- since its established either, has not been well assessed by following se- cacy cannot be reliably rum iron concentrations. Some sources have recommended using resolution of clinical as symptoms such metabolic acidosis as the therapeutic end de- point. Typically, feroxamine is given over about 24 hours. REFERENCES 1. et al. 2004 Annual report Litovitz TL, Rodgers GC Jr, WA, Watson 2. UpToDate.com. Liebelt LL, Kronfol R. Acute iron intoxication. DA. Iron poi- 3. M, Koren G, Redelmeier, Juurlink DN, Tenenbein LI, Delaney KA. : iron, lead, and Velez 4. 5. Effectiveness Krenzelok EP. LW, Oudjhane K, Young Everson GW, 6. Fine JS. . However, it is recom- However, mended that dosing consultation and duration decisions be made in poison with a medical toxicologist or a regional Major adverse effects include hy- control center. adequate potension, which can be controlled with infusion rate, hydration and adjustments to the which and adult respiratory distress syndrome, hours of con- typically occurs after more than 32 tinuous infusion. charcoal, hemodialysis, or hemoperfusion in thecharcoal, hemodialysis, or hemoperfusion treatment of acute iron toxicity. 7. M. Iron. In: Ford MD, Delaney KA, Ling LJ, et al., 7. Tenenbein 4 If peak 4 4 g/dL, and — g/dL, or the — 6 4 sly noted, deferoxamine is a chelat- If an asymptomatic patient has ingested less If an asymptomatic patient has ingested As previou Whole bowel irrigation is done by using a If the patient has ingested more than 20 mg/kg If the patient has ingested more than Deferoxamine challenge via intramuscular in- intramuscular challenge via Deferoxamine

ing agent that binds to iron to form ferrioxamine, a nontoxic compound that is renally excreted. Its optimal dosing and route of administration have not been established, but continuous intra- venous infusion at an initial dose of 15 mg/kg/h THERAPEUTIC CONSIDERATIONS guidelines for the man- There are no consensus the use of whole iron toxicity, agement of acute or obser- bowel irrigation, deferoxamine therapy, but the vation and discharge versus admission, based on following are some recommendations the current evidence. to the than 20 mg/kg of elemental iron according is sufficient and discharge is observation history, the patient’s appropriate if there is no change in condition after 6 hours. polyethylene glycol electrolyte lavage solution. Irrigation should be administered at 1.5 to 2 L/h in adults, 20 to 40 mL/kg/h for children, and should be continued until the rectal effluent is clear. of elemental iron, has visible pills on x-ray, or on x-ray, of elemental iron, has visible pills whole bowel irriga- shows signs of mild toxicity, that peak tion is recommended. Keeping in mind 3 to 5 hours iron concentrations typically occur in sustained- after ingestion, but may be delayed the se- release or enteric-coated formulations, initially and rum iron level should be checked reportedly again 6 to 8 hours after the ingestion occurred to ensure decreasing levels. serum iron levels are less than 300 the patient remains asymptomatic after 6 hours of observation, he or she may be discharged. If peak levels are greater than 500 de- patient shows any signs of systemic toxicity, feroxamine therapy should be initiated. jection is no longer recommended to test for iron to test for no longer recommended jection is form to free iron to Deferoxamine binds ingestion. is (again theoretically) excretedferrioxamine, which it a brick orange discoloration orin the urine to give there appearance. However, the classic “vin rosé” cases in which a deferoxaminehave been multiple no urine discoloration despitechallenge produced toxic serum iron concentrations. www.emedmag.com