Pediatric Iron Toxicity

The absorption of iron is normally very tightly controlled by the gastrointestinal (GI) system. However, in overdose, local damage to the GI mucosa allows unregulated absorption, which leads to potentially toxic serum levels.

Toxicity manifests as local and systemic effects. Typically, iron poisoning is described in 5 sequential phases. No consensus has been reached regarding the number of phases and the times assigned to those phases. Patients may not demonstrate all of the phases, depending in part on the amount of iron ingested.

Phase 1

Phase 1, initial toxicity, predominantly manifests as GI effects. This phase begins during the first 6 hours after ingestion and is associated with vomiting, diarrhea, and abdominal pain. Both hematemesis and hemetachezia may develop, predominantly due to direct local corrosive effects of iron on the gastric and intestinal mucosa. Early hypovolemia may result from GI bleeding, diarrhea, and third spacing due to inflammation. This hypovolemia can contribute to tissue hypoperfusion and metabolic acidosis.

Convulsions, shock, and coma may complicate this phase if the circulatory blood volume is sufficiently compromised. In these cases, the patient progresses directly to phase 3, possibly within several hours.

Phase 2

Phase 2 is known as the latent phase and typically occurs 4-12 hours postingestion. It is usually associated with an improvement in GI symptoms, especially when supportive care is provided during phase 1. During this time, iron is absorbed by various tissues, and systemic acidosis increases. Clinically, the patient may appear to improve, especially to nonmedical personnel, because the vomiting that occurs in phase 1 subsides. However, the vital signs worsen (eg, progressive tachycardia, developing hypotension) and laboratory analysis demonstrates progressive metabolic acidosis and, potentially, the beginning of other end-organ dysfunction (ie, elevation of transaminase levels).

Phase 3

Phase 3 typically begins within 12-24 hours post-ingestion, although it may occur within a few hours after a massive ingestion. Following absorption, ferrous iron is converted to ferric iron, and an unbuffered hydrogen ion is liberated. Iron is concentrated intracellularly in mitochondria and disrupts oxidative phosphorylation, resulting in free radical formation and lipid peroxidation. This exacerbates metabolic acidosis and contributes to cell death and tissue injury at the organ level.

Phase 3 consists of marked systemic toxicity caused by this mitochondrial damage and hepatocellular injury. GI fluid losses lead to hypovolemic shock and acidosis. Cardiovascular symptoms include decreased heart rate, decreased myocardial activity, decreased cardiac output, and increased pulmonary vascular resistance. The decrease in cardiac output may be related to a decrease in myocardial contractility exacerbated by the acidosis and hypovolemia. Free radicals from the iron absorption may induce damage and play a role in the impaired cardiac function.

The systemic iron poisoning in phase 3 is associated with a positive anion gap metabolic acidosis. The following explanations for the acidosis have been proposed:

• Conversion of free plasma iron to ferric hydroxide is accompanied by a rise in hydrogen ion concentration.

• Free radical damage to mitochondrial membranes prevents normal cellular respiration and electron transport, with the subsequent development of lactic acidosis.

• Hypovolemia and hypoperfusion contribute to acidosis.

• Cardiogenic shock contributes to hypoperfusion.

A coagulopathy is observed and may be due to two different mechanisms.  First, free iron may exhibit a direct inhibitory effect on the formation of thrombin and thrombin's effect on fibrinogen in vitro. This may result in a coagulopathy. Later, reduced levels of clotting factors may be secondary to hepatic failure.

Phase 4

Phase 4 may occur 2-3 days postingestion. Iron is absorbed by Kupffer cells and hepatocytes, exceeding the storage capacity of ferritin and causing oxidative damage. Pathologic changes include cloudy swelling, periportal hepatic necrosis, and elevated transaminase levels. This may result in hepatic failure.

Phase 5

Phase 5 occurs 2-6 weeks postingestion and is characterized by late scarring of the GI tract, which causes pyloric obstruction or hepatic cirrhosis. See the image below.

As with any ingestion, the risk of ingestion increases as the availability of the medication increases. One study found an association between iron poisoning in young children and recent birth of a sibling.[3]  Childproof containers for multivitamins and prenatal vitamins may be of some assistance in decreasing exposure. The introduction of unit-dose packaging was followed by a decrease in the incidence of nonintentional ingestion of iron by young children and a decrease in mortality from iron poisoning.[4]  

Frequency

United States

In 2018, the American Association of Poison Control Centers (AAPCC) reported 4459 single exposures to iron and iron salts: 2173 were in children  aged 5 years and younger, 156 in children 6 to 12 years old, and 540 in patients 13 to 19 years old. In addition, the AAPCC reported thousands of exposures to multivitamins with iron in children.[5]   

Age

Most exposures involve children younger than 6 years who have ingested pediatric multivitamin preparations. Many of the serious acute ingestions follow the pattern of ingestions in general and occur in children younger than 3 years.

Most exposures result in minimal toxicity. However, concentrated iron supplement overdoses can result in serious sequelae and death.

If a patient does not develop symptoms of iron toxicity within 6 hours of ingestion, iron toxicity is unlikely to develop. Expect clinical toxicity following an ingestion of 20 mg/kg of elemental iron. Expect systemic toxicity with an ingestion of 50 mg/kg. Ingestion of more than 250 mg/kg of elemental iron is potentially lethal.

Complications of iron toxicity include the following:

• Infectious - Yersinia enterocolitica septicemia
• Pulmonary - Acute respiratory distress syndrome (ARDS)
• Gastrointestinal - Fulminant hepatic failure, hepatic cirrhosis, pyloric or duodenal stenosis

Susceptibility to Yersinia enterocolitica infection or sepsis is heightened in these patients because Yersinia requires iron as a growth factor. Deferoxamine acts to solubilize iron and aid in intracellular entry for Yersinia. Suspect Yersinia infection in patients who develop abdominal pain, fever, and diarrhea following resolution of iron toxicity.

Educate parents about the need for childproofing the home and keeping medications out of reach of children. For patient education information, see First Aid for Poisoning in Children, Child Safety Proofing, and Iron Poisoning Treatment.

Pediatric iron poisonings are typically unintentional. Children may ingest the iron prescribed to mothers as prenatal vitamins or postpartum supplements. Other iron exposures include ingestion of iron-fortified children's vitamins, although these tend to be less toxic. Parents may not immediately be aware of the ingestion or the specific number of iron pills ingested.

If possible, determine the number of pills ingested, how much iron was in each pill, and the percentage of iron in the supplement. Different formulations of iron contain varying amounts of elemental iron, as follows:

• Ferrous gluconate- 12% elemental iron
• Ferrous lactate - 19% elemental iron
• Ferrous sulfate - 20% elemental iron
• Ferrous chloride - 28% elemental iron
• Ferrous fumarate - 33% elemental iron

The following is a formula used to calculate the amount of ingested iron for a 10-kg child who consumed 10 tablets of 320 mg ferrous gluconate (12% elemental iron per tablet):

320 mg ferrous gluconate × 0.12 elemental iron per tablet = 38.4 mg elemental iron per tablet × 10 tablets = 384 mg/10 kg = 38.4 mg/kg

Carbonyl iron and iron polysaccharide complex are nonionic forms of iron that have less toxicity than ferrous salts.

Attempt to determine the time of ingestion. This is important in determining observation periods and timing of serum levels.

As stated in Pathophysiology, iron toxicity is typically described in 5 sequential phases. Universal agreement does not exist as to the number of phases or the times assigned to those phases. Patients may not always demonstrate each of the phases.

Few, if any, physical examination findings are specific to iron toxicity. Overall findings tend to vary by phase, as follows:

• Phase 1 usually occurs within the first 6 hours postingestion. This phase is associated with abdominal pain, vomiting, and diarrhea, which may be hemorrhagic due to mucosal injury. The hemorrhagic GI symptoms are due to the direct effects of iron on the GI mucosa. A patient is unlikely to develop significant systemic toxicity without first having GI symptoms. In severe cases, the GI losses of blood and fluid may be massive and lead to shock and coma.

• Phase 2 usually occurs 6-12 hours postingestion and may be associated with an improvement in symptoms, especially when supportive care has been provided during phase 1. This period of apparent recovery may be confusing. In mild cases, this recovery may represent true recovery. However, in serious ingestions, it may represent only a temporary respite or may not occur at all; the patient may progress directly to phase 3. The etiology of phase 2 is unclear, but it may represent the time it takes for iron to distribute throughout the body and for systemic injury to occur. The only findings on examination may be lethargy, mild tachycardia, or tachypnea.

• Phase 3 begins after 12-24 hours postingestion and consists of multisystem damage. This may include marked metabolic acidosis, coagulopathy, shock, seizures, and altered mental status due to mitochondrial damage and hepatocellular injury.

• Phase 4 occurs 2-3 days postingestion and is characterized by hepatic injury.

• Phase 5 occurs 2-6 weeks postingestion and is characterized by late scarring of the GI tract, which causes pyloric obstruction or hepatic cirrhosis. However, these complications are rare, even in severe cases.

Caregivers and clinicians may be falsely reassured by the cessation of GI symptoms. It is important to assess for subtle vital sign abnormalities (such as tachypnea and/or tachycardia) as a sign that metabolic changes may be occurring, to avoid discharging the patient prematurely.

Clinicians should also assess for possible co-ingestants or other substances in the household, so as to not miss a concurrent toxicity.

Iron toxicity is a clinical diagnosis; any studies are simply adjuncts. Toxic effects of iron may occur at doses of 10-20 mg/kg of elemental iron.

Little is known about the absorption rate of iron in an overdose, the timing of peak serum iron levels, or the rate at which serum levels fall from their peak levels. Serum iron levels generally correlate with clinical severity and are as follows:

• Mild - Less than 300 µg/dL
• Moderate - 300-500 µg/dL
• Severe - More than 500 µg/dL

Difficulties involved with interpretation of serum iron levels include the following:

• The ideal serum iron level is a peak level at 2-6 hours postingestion, and the time from ingestion is often unknown.

• Deferoxamine interferes with standard assays and leads to falsely decreased iron levels.

• Serum iron levels may not be available in a timely fashion. Serum levels obtained more than 8-12 hours postingestion may not be useful because iron redistributes into the tissues and the serum level does not reflect the total body burden of iron.

Total iron-binding capacity (TIBC) has traditionally been used to determine toxicity. Previously, a patient with a serum iron level greater than the TIBC was thought to be at risk for developing systemic toxicity. However, determining the TIBC in the presence of large amounts of iron or deferoxamine may yield a falsely elevated number. Hence, a TIBC above the iron level does not indicate sufficient binding capacity, and this test is not useful in determining the likelihood of toxicity.[7]

Because iron levels are not always readily available, the predictive value of other laboratory test results has been explored. Previously, a white blood cell count greater than 15,000/µL and a serum glucose level greater than 150 mg/dL were said to correlate with iron levels greater than 300 µg/dL. However, more recent studies do not support the predictive value of these ancillary tests, and they are not useful in the setting of iron poisoning.

Abdominal radiography may offer information on the iron ingestion, both initially and subsequently. Do not delay treatment for radiography. An initial negative radiographic finding may mean that no iron was ingested or that the ingested iron tablets or solution have dissolved. In addition, liquid preparations and chewable vitamins are not visible on radiographs.

A positive radiographic finding is one that shows radiopaque tablets or particles. This indicates that the ingested iron has not been completely absorbed. Obtaining a radiograph before and after GI decontamination may yield information as to the success of therapy. If the radiographic findings remain positive after decontamination, additional decontamination is required. If the radiographic findings were initially positive and are negative after GI decontamination, this indicates that GI decontamination was successful, although iron levels should still be monitored because of iron absorption prior to initiation of therapy.

The deferoxamine challenge test consists of administering a single dose of deferoxamine, which binds available free iron and is excreted in the urine as the ferrioxamine complex (deferoxamine and iron). This complex changes the urine to a reddish (vin rosé) color, indicating the need for chelation. However, the urine does not change color reliably, even when elevated serum iron levels are present.

This test is not reliable and does not eliminate the need for monitoring serum iron levels. Therefore, one should not rely on the deferoxamine challenge test.

Asymptomatic patients may be monitored at home in collaboration with the local poison control center. Observation at home can also be used for patients who have ingested less than 40 mg/kg of elemental iron and who are having mild symptoms (eg, nausea, vomiting). Patients who have ingested children's chewable vitamins plus iron or carbonyl iron or polysaccharide-iron complex formulations should be observed at home with appropriate follow-up.[8]

Children who are symptomatic after an iron ingestion should have intravenous access established and laboratory monitoring for acidosis and anemia from hemorrhagic  gastrointestinal (GI) losses.

If an iron level is readily available from the laboratory, this should be obtained, and may need to be trended if the lab is obtained less than 6 hours after the ingestion.

Treatment with intravenous deferoxamine should be considered for iron levels >500 µg/dL, significant acidosis, or ongoing symptoms.

An abdominal x-ray may suggest the need for whole bowel irrigation if radioopaque fragments are visible. Endoscopic or surgical removal may be considered if retained iron tablets are evident after GI decontamination.

The first step in treating a case of acute iron toxicity is to provide appropriate supportive care, with particular attention paid to fluid balance and cardiovascular stabilization. Initial treatment should also address the issue of preventing further absorption of iron by the GI tract.

Ipecac-induced emesis is not recommended. This is especially true in iron ingestion, as GI distress is an early finding in iron poisoning and is present in all potentially serious ingestions, and ipecac-induced vomiting may cloud the clinical picture. In any event, ipecac is rapidly becoming unavailable, and since 2003 is no longer recommended to be kept in the home by the American Academy of Pediatrics.[9]

Gastric lavage is not recommended because iron tablets are relatively large and become sticky in gastric fluid, making lavage unlikely to be of benefit. In addition, the physical placement of a lavage tube into friable mucosa may predispose to perforation. Activated charcoal is also not effective as it does not adsorb iron.

Whole bowel irrigation has been used to speed the passage of undissolved iron tablets through the GI tract, although there is no convincing evidence from clinical studies that it improves the outcome.[10] A polyethylene glycol electrolyte solution (eg, GoLYTELY) may be administered orally or nasogastrically at a rate of 250-500 mL/h for toddlers and preschoolers and 2 L/h for adolescents. It is recommended to start the irrigation slowly, increasing as tolerated, and provide antiemetics as needed. Continue irrigation until the repeat radiographic findings are negative or rectal effluent is clear.

Deferoxamine is the iron-chelating agent of choice. Deferoxamine binds absorbed iron, and the iron-deferoxamine complex is excreted in the urine. Deferoxamine does not bind iron in hemoglobin, myoglobin, or other iron-carrying proteins. Base the indications for using deferoxamine on both clinical and laboratory parameters. Indications for treatment include shock, altered mental status, persistent GI symptoms, metabolic acidosis, pills visible on radiographs, serum iron level greater than 500 µg/dL, or estimated dose greater than 50 mg/kg of elemental iron. Initiate chelation if a serum iron level is not available and symptoms are present.

Deferoxamine may be administered intramuscularly or intravenously. The intramuscular route is not recommended because it is painful and less iron is excreted compared with the intravenous route. Intravenously, deferoxamine is given as a continuous infusion. The standard dose is 15 mg/kg/h, with an initial dose administered for 6 hours.[11]  There is no role for oral deferoxamine.

No clear end point of therapy is noted; however, indications for cessation include significant resolution of shock and acidosis. Infusion of deferoxamine for 6-12 hours has been suggested for moderate toxicity. For severe toxicity, administer deferoxamine for 24 hours. Because these end points are arbitrary, observe the patient for the recurrence of toxicity 2-3 hours after the deferoxamine has been stopped.

Adverse effects from deferoxamine are unusual. Pulmonary toxicity (ie, acute respiratory distress syndrome [ARDS], tachypnea) has been described, especially if patients are treated with deferoxamine for more than 24 hours. Rate-related hypotension can occur. Therefore, monitor the patient while titrating the infusion rate upward to a final rate of 15 mg/kg/h, and ensure hydration has been initiated prior to starting the infusion.[12]

If retained iron tablets are evident after GI decontamination, consider endoscopy or surgery for their removal. Failure to remove the iron can result not only in continued iron absorption and exacerbation of systemic symptoms but also in gastric perforation and severe hemorrhage. Cases of GI perforation should prompt emergent surgical evaluation.

Regional poison control centers may be contacted for assistance in patient management (1-800-222-1222). In addition, consult an intensivist for help in managing the moderately to severely ill child. Admission to a pediatric intensive care unit is indicated for patients who present with signs and symptoms of significant iron poisoning, such as metabolic acidosis, potential hemodynamic instability, and/or lethargy.

As mentioned above, treatment with deferoxamine has been associated with ARDS, albeit in rare cases.  Patient should be monitored for signs of respiratory distress or increased work of breathing during their treatment.

After treatment with deferoxamine, certain bacterial overgrowth may occur. Yersinia enterocolitica septicemia has been reported after iron overdoses. Yersinia uses iron as a siderophore for growth and its growth is further enhanced by treatment with deferoxamine.[13]

Most iron ingestions are accidental. As for any medication, preventive measures include keeping the bottles of iron supplements, with childproof tops, inaccessible to children. Changing the appearance of prenatal vitamins to make them look less like candy has been considered. This would be ideal.

In 1997, the US Food and Drug Administration (FDA) issued a regulation requiring unit-dose packaging for iron-containing products with 30 mg or more of iron per dosage unit. Because of the time and effort to open unit-dose packages, the FDA believes this packaging limits unintentional access to children. This requirement was in addition to existing Consumer Product Safety Commission regulations that require child-resistant packaging for most iron-containing products. In 2003, this requirement was rescinded because of a lawsuit in which the National Health Alliance charged that the FDA had no jurisdiction over the packaging of dietary supplements.

The goals of pharmacotherapy are to reduce iron levels, prevent complications, and reduce morbidity. Deferoxamine (Desferal) is used for chelation of iron in both acute and chronic toxicity.

The oral chelating agent deferasirox (Exjade) is approved by the US Food and Drug Administration (FDA) for the treatment of chronic iron overload due to blood transfusions in patients 2 year of age and older; it is also approved for treatment of chronic iron overload resulting from non–transfusion-dependent thalassemia.

Class Summary

Deferoxamine is a specific iron chelator. In the presence of ferric iron, deferoxamine forms the complex ferrioxamine, which is excreted by the kidneys. This complex imparts a reddish, vin rosé, color to the urine. Deferoxamine does not bind iron that is present in hemoglobin, hemosiderin, or ferritin. Deferoxamine is a parenteral iron chelator. It is administered IV or IM in the management of acute iron toxicity.

Deferoxamine mesylate (Desferal)

Freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. Most effective when continuously provided to the circulation by infusion. May be administered either by IM injection or by slow IV infusion. Does not effectively chelate other trace metals of nutritional importance. Provided in vials containing 500 mg or 2 g of lyophilized sterile drug. Add 2 mL or 8 mL of sterile water for injection to each vial, bringing the concentration to 250 mg/mL. For IV use, this may be diluted in 0.9% sterile saline, 5% dextrose solution, or Ringer solution.

Deferasirox (Exjade)

Tab for PO susp. PO iron chelation agent demonstrated to reduce liver iron concentration in adults and children who receive repeated RBC transfusions. Binds iron with high affinity in a 2:1 ratio. Approved to treat chronic iron overload due to multiple blood transfusions. Treatment initiation recommended upon evidence of chronic iron overload (ie, transfusion of about 100 mL/kg packed RBCs [about 20 U for 40-kg person] and serum ferritin level consistently >1000 µg/L).

Class Summary

Polyethylene glycol is used to increase GI transit time, decreasing absorption. It is not absorbed and is excreted entirely through the GI tract.

Polyethylene glycol (GoLYTELY, NuLytely, Colovage, Colyte)

Laxative with strong electrolyte and osmotic effects that has cathartic actions in GI tract.