Pediatric Iron Poisoning

Pediatric Iron Poisoning Review the clinical management of an acute iron poisoning. journalArticle pediatrics,pediatric, primary care,pharmacists Bruce D. Anderson, PharmD Bruce D. Anderson, PharmD, Director of Operations, Maryland Poison Center and Assistant Professor, University of Maryland, Baltimore, School of Pharmacy. Medscape Portals, Inc Medscape Pharmacists 04/10/2000 1 1 <H4>Introduction</H4> Iron is one of the leading causes of pediatric poisoning deaths in the United States.[1] Numerous case series and reports of serious or fatal iron poisoning have been cited in the medical literature,[1-3] including 5 toddler deaths in Los Angeles county during a 7-month period in 1992.[4] While it is clear that iron can cause serious morbidity and mortality, many families and even some clinicians are unaware of the dangers of iron.<H4>General Toxicology</H4> Iron is an essential trace mineral vital to cellular respiration and to hemoglobin formation. Humans have developed complex mechanisms for absorbing and safely utilizing iron from a normal diet. In overdose, large amounts of ingested iron overwhelm normal gastrointestinal (GI) barriers, resulting in massive iron absorption. When serum iron levels exceed the body's ability to bind the absorbed iron, deposition of free iron in the tissues occurs. Free iron can produce oxidative damage in whatever cells it encounters.Pharmacokinetics[5] Absorption. Although uncommon, iron solutions may be absorbed through damaged or burned skin. Following ingestion of large amounts of iron, peak serum levels generally occur within 2 to 6 hours. Serum levels drawn more than 6 hours after ingestion may underestimate the degree of potential toxicity because of distribution of the iron out of the vascular compartment. In some cases, iron tablets may clump in the GI tract, leading to iron concretions (bezoars) and delayed absorption. In addition, there are several sustained-release iron preparations on the market that may also delay absorption.Distribution. After ingestion, iron in the +2 state is oxidized to the +3 state and attached to the storage protein, ferritin. The iron is then released from the ferritin to transferrin in the plasma, transported to the blood-forming and storage sites, and incorporated into enzymes in the body.Elimination. Iron is eliminated slowly from the body. Even in states of iron overload, children may lose only up to 2 mg per day. Range of Toxicity Ingestions of < 20 mg/kg elemental iron are likely to produce only self-limiting GI symptoms. Ingestions of between 20 and 60 mg of elemental iron often produce more severe GI symptoms. For patients who ingest > 60 mg/kg elemental iron, potentially life-threatening symptoms may occur. The exact lethal dose of iron is not well known. However, the vast majority of cases of fatal iron overdose have involved ingestions of well over 250 mg/kg elemental iron.[4] Table 1 lists some of the commercially available products and iron content.<H4>Patient Presentation</H4> The presentation of iron poisonings has traditionally been separated into 5 stages, although many patients do not follow this pattern. NOTE: Times listed for development of symptoms are approximate.Stage 1 occurs within the first 30 minutes to 2 hours of the exposure. This stage is generally characterized by GI symptoms: nausea, vomiting, diarrhea, and possibly gastric hemorrhage. In the case of exposure to large amounts of iron, central nervous system (CNS) depression can occur.Stage 2 has been described as a period of apparent improvement or quiescence that may be misleading. Please note that this stage is rarely encountered in most serious iron overdose cases. Most patients with serious iron overdose have symptoms throughout the course of their overdose.Stage 3 occurs between 2 and 12 hours after ingestion; during this stage, patients may start to show signs of more serious systemic toxicity (hypotension, cyanosis, CNS depression) along with continued local GI effects.Stage 4 occurs around days 2 to 4 postexposure, when systemic toxicity becomes more prominent. Free iron can produce damage in all organs, especially those with high blood flow. Hepatic and renal damage become evident, patients frequently develop metabolic acidosis, alterations in coagulation may be seen, respiratory compromise may develop, and CNS depression can occur.Stage 5 patients who survived the previous 4 stages may go on to develop additional effects. Between 2 to 4 weeks postexposure, intestinal obstruction may be seen. This is caused by the local corrosive effects of iron on the GI tract, which produces scarring. If the corrosive effects develop in a circumferential pattern, gastric obstruction may occur. NOTE: This is a rare effect.Laboratory Assessment Iron has complex pharmacokinetics/dynamics, especially in overdose. Serum iron levels should be drawn between 2 and 6 hours after ingestion to obtain a peak serum iron level. Peak iron concentrations correlate best as predictors of toxicity. Because iron has multicompartment distribution, serum levels obtained after 6 to 8 hours may appear falsely low because of distribution of iron into the tissues. Please note that iron absorption may be prolonged or delayed, owing to the formation of bezoars (a concretion of tablets) or ingestion of sustained-release preparations. Multiple serum iron concentrations are necessary to adequately manage serious iron poisoning cases. For many years, measurement of total iron binding capacity (TIBC) was suggested along with the serum iron measurement as a method of identifying the specific individual's ability to bind iron. Theoretically, if the serum iron level was lower than the TIBC, then there would be no free iron to produce toxicity. More current research has shown that in the presence of high serum iron values, the TIBC may be falsely elevated.[6] Because of the difficulty interpreting these results, measurement of the TIBC is not currently recommended in the management of patients with acute iron overdose. Peak serum iron concentrations of > 350 mcg/dL are generally associated with mild to moderate toxicity. Concentrations > 500 mcg/dL are associated with more serious toxicity. Because of the complex pharmacokinetics of iron, it is extremely difficult to interpret nonpeak iron levels. There are rare case reports in the literature of patients who have died with "peak" blood levels < 400 mcg/dL.[7] In these instances, the "peak" level has been obtained much later than 6 hours postingestion. In the past, when rapid availability of serum iron concentrations was not common, clinicians looked for other proxy indicators of iron poisoning. In one study, a white blood cell count > 15,000/mm3 and a blood glucose > 150 mg/dL was associated with serum iron concentrations of > 300 mcg/dL.[8] Follow-up studies have not been able to validate these findings.[9] These proxy indicators should not be used when serum iron can be measured. Other laboratory values that should be obtained include complete blood count (CBC), electrolytes, arterial blood gases, liver and renal function, prothrombin time, and partial thromboplastin time (PTT).Patient Disposition Ingestions < 20 mg/kg are generally not associated with the development of serious symptoms and require only observation at home. Ingestions of 20 to 60 mg/kg frequently produce mild to moderate toxicity and may be managed with emesis at home and close observation with referral to a healthcare facility if further symptoms develop. Ingestions > 60 mg/kg may produce serious toxicity, and patients should be referred to a healthcare facility for definitive care.[10] NOTE: Ingestions of children's chewable vitamin tablets containing < 20 mg of elemental iron per tablet have not been associated with severe toxicity, even when large numbers of tablets have been ingested.[11,12]<H4>General Management</H4> Supportive therapy using standard Advanced Cardiac Life Support (ACLS) guidelines may be necessary in cases of serious iron overdose. Because of large fluid losses and potential development of hypotension, large-bore intravenous access may be necessary. <H4>Specific Management</H4> Gastric Decontamination<OL><LI>Vomiting may be induced with ipecac syrup if the patient is alert and cooperative and the ingestion occurred within 30 to 60 minutes or if an abdominal x-ray shows the presence of tablets in the stomach. However, ipecac does not consistently remove all iron tablets from the stomach. <LI>If emesis is contraindicated, gastric lavage may be considered using a large-bore orogastric tube. Unfortunately, because of the size of most adult forms of iron, the largest-bore lavage tube may not allow passage of iron tablets through the lumen of the tube. NOTE: There is no evidence that bicarbonate or phosphate lavage solutions provide any additional benefit over saline or tap water, and both these solutions have been associated with the production of severe and life-threatening electrolyte abnormalities.[13] Oral administration of deferoxamine has been shown experimentally in humans and in some animal models to promote the absorption of iron from the GI tract and therefore should not be used.[14]<LI>Whole bowel irrigation using polyethylene glycol plus electrolyte solution (eg, Golytely, Colyte) should be used as an alternative to emesis and lavage, particularly if large numbers of tablets are visible on x-ray past the stomach.[15]<LI>Activated charcoal does not bind iron and should not be given unless coingestants are involved that may be bound by charcoal. An abdominal x-ray should be obtained to determine the presence of any remaining tablets in the GI tract following GI decontamination procedures. A serum iron level should be drawn within 6 hours of ingestion following GI decontamination procedures. In a small number of cases where x-ray has shown a bezoar of iron tablets in the GI tract, surgical removal of the tablets has been performed.[16] This should be considered if a clump of tablets can be seen on x-ray and they fail to move or break up with the usual procedures. Endoscopy has rarely been successfully used to break up clumps of tablets in the stomach. </OL>Chelation If the patient is symptomatic or if the serum iron is > 500 mcg/dL, start deferoxamine (Desferal) 15 mg/kg/hr IV. IV therapy is preferred to ensure complete absorption. If the serum iron is < 500 mcg/dL, the abdominal x-ray is negative, and the patient is asymptomatic, the likelihood of serious toxicity is low. There are several caveats related to use of deferoxamine that need to be highlighted. Rapid infusion of deferoxamine has been associated with hypotension. The maximum initial rate for deferoxamine should be 15 mg/kg/hr. Neurologic toxicity has been reported as well, primarily ocular toxicity.[17] The manufacturer states that the maximum dose of deferoxamine is 6 g/day. However, deferoxamine 1 g only binds ~ 90 mg of elemental iron. Six grams of deferoxamine may not be adequate in a severe poisoning in an adult. Some authors have suggested that patients receiving deferoxamine therapy for > 24 hours are at increased risk of severe respiratory symptoms (eg, acute respiratory distress syndrome [ARDS]).[18] Because ARDS is a common complication of iron overdose, it is difficult to establish true cause and effect. However, an animal model has demonstrated a possible mechanism of pulmonary injury secondary to iron-deferoxamine complex.[19] Consult the regional poison center for consideration of the duration of therapy. Although listed as a Category C substance (meaning that studies have shown that the drug exerts animal teratogenic or embryocidal effects, but no controlled studies in women have been conducted, or no studies are available in either animals or women), pregnancy is not a contraindication to deferoxamine therapy. There is some evidence that deferoxamine given to rodents experimentally has a moderate teratogenic effect on the fetus. Therefore, the theoretical risk of therapy in the first trimester must be weighed against the risk of nontreatment. In moderate to severe iron poisoning, the risk of not treating will outweigh any potential teratogenic risk to the fetus, and deferoxamine should not be withheld. In patients with iron-induced injury to the GI tract, treatment with deferoxamine, particularly by the oral route, may predispose them to sepsis with Yersinia enterocolitica. The deferoxamine functions as a siderophore for this organism, stimulating its growth and enhancing its virulence. Exchange Transfusions and Hemodialysis Exchange transfusions have occasionally been used in severe iron overdose cases, and only in very young pediatric patients. Hemodialysis, hemoperfusion, and other extracorporeal procedures will not remove iron; however, hemodialysis will remove ferrioxamine, the iron chelate, and may be required in patients in renal failure. If hemodialysis is performed, it must be noted that this procedure will also remove deferoxamine. <H4>Summary</H4> Recently, enhanced awareness of the toxicity of iron has resulted in changes in packaging and labeling. These regulatory changes require that iron-containing products with >/= 30 mg iron per dosage unit (tablet, capsule, caplet, etc) be packaged in "unit-dose packaging" such as a "blister-pack," pouch, or other nonreusable container. The regulation temporarily exempts products that contain >/= 30 mg of an elemental form of iron, which is called carbonyl iron, from the unit-dose packaging requirements. The reason for the temporary exemption is that preliminary data indicate that this form of iron may be so much less toxic than iron salts that accidental overdose of these products is unlikely to result in serious injury or death. For low-dose products (ie, products with < 30 mg of iron per dosage unit) that are not packaged in unit-dose packaging (eg, for tablets packaged in a bottle), the regulation requires that the warning statement appear prominently and conspicuously on the information panel of the immediate container label (ie, on the label of the bottle that holds the tablets). These efforts to limit access of iron products to children plus efforts to raise awareness of the toxicity of iron have been associated with a decrease in fatal iron overdoses reported by poison centers in the United States. In 1991, 14 deaths from iron products in children younger than age 6 were reported to poison centers. In 1998 (the most current data available), there were no reported deaths in children from iron-containing products.[20] Additional vigilance and awareness are necessary to prevent children from becoming victims of iron poisoning. <h3><a name="Table 1.">Table 1. Iron Content of Commercially Available Products</h3></a> <blockquote><TABLE BORDER="1" CELLPADDING="3"><TR valign="TOP" align="left"><TD colspan=1 align="left">Product</TD><TD colspan=1 align="left">Iron salt</TD><TD colspan=1 align="left">Elemental Iron</TD></TR><TR valign="TOP" align="left"><TD colspan=1 align="left">Flintstone plus iron </TD><TD colspan=1 align="left">Fumarate </TD><TD colspan=1 align="left">15 mg </TD></TR><TR valign="TOP" align="left"><TD colspan=1 align="left">FeoSol Spansules </TD><TD colspan=1 align="left">Sulfate </TD><TD colspan=1 align="left">50 mg </TD></TR><TR valign="TOP" align="left"><TD colspan=1 align="left">Fergon </TD><TD colspan=1 align="left">Gluconate </TD><TD colspan=1 align="left">36 mg </TD></TR><TR valign="TOP" align="left"><TD colspan=1 align="left">Feostat </TD><TD colspan=1 align="left">Sulfate </TD><TD colspan=1 align="left">33.3 mg </TD></TR><TR valign="TOP" align="left"><TD colspan=1 align="left">Fer-In-Sol Syrup </TD><TD colspan=1 align="left">Sulfate </TD><TD colspan=1 align="left">18 mg/5 mL </TD></TR></TABLE></blockquote> <OL><LI>Litovitz TL, Holm KA, Bailey KM, Schmitz BF. 1991 Annual Report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med. 1992;10:452-505. <LI>Westlin WF. Deferoxamine in the treatment of acute iron poisoning. Clin Pediatr. 1966;5:531-535. <LI>Henriksson P, Nilsson L, Nilsson IM, Stenberg P. Fatal iron intoxication with multiple coagulation defects and degradation of factor VIII and factor XIII. Scand J Haematol. 1979;22:235-240. <LI>Weiss B, Alkon E, Weindlar F, Kelter A, Delacruz P. Toddler deaths resulting from ingestion of iron supplements - Los Angeles, 1992-1993. MMWR Morb Mortal Wkly Rep. 1993;42:111-113. <LI>Harju E. Clinical pharmacokinetics of iron preparations. Clin Pharmacokinet. 1989;17:69-89. <LI>Burkhart KK, Kulig KW, Hammond KB, Pearson JR, Ambruso D, Rumack B. The rise in total iron binding capacity after iron overdose. Ann Emerg Med. 1991;20:532-535. <LI>Westlin W. Deferoxamine in the treatment of acute iron poisoning: clinical experiences with 172 children. Clin Ped. 1966;5:531-535. <LI>Lacouture PG, Wason S, Temple AR, et al. Emergency assessment of severity in iron overdose by clinical and laboratory methods. J Pediatr. 1981;99:89-91. <LI>Palatnick W, Tenenbein M. Leukocytosis, hyperglycemia, vomiting, and positive x-rays are not indicators of severity of iron overdose in adults. Am J Emerg Med. 1996;14:454-455. <LI>Klein-Schwartz W, Oderda GM, Gorman R, Favin F, Rose SR. Assessment of management guidelines: acute iron ingestion. Clin Pediatr. 1990;29:316-321. <LI>Anderson BD, Turchen SG, Manoguerra AS. Seven year review of children's chewable multivitamin plus iron ingestions [abstract]. Vet Hum Toxicol. 1993;35:370. <LI>Dean BS, Krenzelok EP. Multiple vitamins and vitamins with iron: accidental poisoning in children. Vet Hum Toxicol. 1988;30:23-24. <LI>Geffner ME, Opas LM. Phosphate poisoning complicating treatment for iron ingestion. Am J Dis Child. 1980;134:509-510. <LI>Whitten CF, Gibson GW, Good MH, Goodwin JF, Brough AJ. Studies in acute iron poisoning. 1. Deferoxamine in the treatment of acute iron poisoning: clinical observations, experimental studies, and theoretical considerations. Pediatrics. 1965;36:322-335. <LI>Everson GW, Bertaccini EJ. O'Leary J. Use of whole bowel irrigation in an infant following iron overdose. Am J Emerg Med. 1991;9:366-369. <LI>Tenenbein M, Wiseman N, Yatscoff RW. Gastrotomy and whole bowel irrigation in iron poisoning. Pediatr Emerg Care. 1991;7:286-288. <LI>Bene C, Manzler A, Bene D, Kranias G. Irreversible ocular toxicity from single "challenge" dose of deferoxamine. Clin Nephrol. 1989;31:45-48. <LI>Tenenbein M, Kowalski S, Sienko A, Bowden D, Adamson IYR. Pulmonary toxic effects of continuous desferrioxamine administration in acute iron poisoning. Lancet. 1992;339:699-701. <LI>Adamson IY, Sienko A, Tenenbein M. Pulmonary toxicity of deferoxamine in iron-poisoned mice. Toxicol Appl Pharmacol. 1993;120:13-19. <LI>Litovitz TL, Klein-Schwartz W, Caravati EM, Youniss J, Crouch B, Lee S. 1998 Annual Report of the American Association of Poison Control Toxic Exposure Surveillance System. Am J Emerg Med. 1999;17:435-487. </OL>