Acute poisoning may occur following accidental, unintentional, or inadvertent ingestion of medications that contain iron. Although acute iron poisoning occurs relatively infrequently, pediatricians should be aware of the presentation and treatment of iron poisoning. The management of acute iron poisoning has changed significantly over the past several years. This article reviews the epidemiology of acute iron poisoning in children, the various formulations of iron, the toxic dose of iron, the clinical presentation and pathophysiology of iron poisoning, and recent changes in evaluating and treating the patient.
Acute iron poisoning is primarily a pediatric phenomenon. In 1993, the American Association of Poison Control Centers reported 24,209 cases of exposure to iron-containing products, of which 84% occurred in children younger than 6 years of age and 10% in children 6 to 19 years of age.1 In 1993, iron exposures accounted for 2.2% of all exposures in children younger than 6 years of age. Interestingly, this percentage has not changed much during the past decade; since 1984, iron has accounted for an average of 2% of all exposures in children 6 years of age and younger (Figure I).1-10
Iron-containing products can be divided into three therapeutic classes: adult iron supplements, adult vitamins with iron, and pediatric vitamins with iron. Table 1 demonstrates the 1993 distribution of exposures to these classes of medications by age group.1 Fortunately, most of these exposures are relatively benign. The outcomes of these cases (including the adults) were classified as none or minor in 90.5%, moderate in 8.5%, major in 0.9%, and death in 0.1%. Of the five fatal cases in 1993, three occurred in children younger than age 6. For this age group, this represents a fatality rate (fatalities/exposure) of 0.038%.
It is interesting to note that serious morbidity has risen steadily from 1984 to 1993 (Figure 2) while the mortality rate (Figure 3) generally has remained steady (except for the years 1990 through 1992).110 The extraordinarily high mortality rates in 1990 (0.063%), 1991 (0.122%), and 1992 (0.074%) have not been explained. The cause of these deaths has been attributed to adult iron formulations. Aggregate data from the American Association of Poison Control Centers demonstrates that 74% of fatalities in young children occurred following the ingestion of adult iron supplements with the balance involving adult vitamins with iron (Table 2).110 No fatalities have been attributed to pediatric vitamins with iron.
Figure 1. Annual iron cases as a percent of all cases for age <6 years.
Figure 2. Morbidity trends for all ages (all cases of moderate or major outcomes/exposure to all forms of medicinal iron).
FORMULATIONS AND TOXIC DOSES
Medicinal iron formulations are comprised of different iron complexes (eg, ferrous sulfate). For toxicology purposes, estimates of ingested iron doses are based on the amount of elemental iron in the particular iron complex. Table 3 lists the iron complexes and their percentages of elemental iron. The most common iron complexes are ferrous gluconate (12%), ferrous sulfate (20%), and ferrous fumarate (33%). To calculate the amount of elemental iron ingested, the amount of the iron complex is multiplied by the percentage of elemental iron in the complex. For example, an individual who has ingested 15 tablets each containing 325 mg ferrous sulfate has taken a total dose of 4875 mg of ferrous sulfate. The amount of elemental iron is calculated by multiplying 4875 mg of ferrous sulfate by 20%. The amount of elemental iron ingested is 975 mg.
Once the amount of ingested elemental iron has been calculated, a judgment must be made as to whether that amount constitutes a potentially toxic dose. Unfortunately, the dose of iron that is considered toxic is not clear-cut and usually is qualified by terms such as "likely" or "possibly". Proposed toxic doses of elemental iron range from 20 mg/kg to >60 mg/kg. The low end of the range is associated primarily with gastrointestinal irritation11 while systemic toxicity occurs at the high end.
The clinical course of acute iron poisoning is classically described as occurring in sequential phases or stages. Although there is no universal agreement about the number of phases or the times assigned to them, it is generally acknowledged that patients may not always demonstrate each of the stages. Table 4 presents a typical sequence with the time postingestion indicating the approximate time interval within which the clinical effects may begin.12,13
Following the ingestion of a toxic amount of iron, gastrointestinal symptoms are the first to appear and should become evident within 6 hours. It is unlikely that a patient will develop significant systemic toxicity without first having suffered gastrointestinal symptoms. In severe cases, the gastrointestinal losses of blood and fluid may be massive and lead to shock and coma. The hemorrhagic gastroenteritis that occurs is due to the direct effects of iron on the gastrointestinal mucosa. The direct corrosive effect of iron accounts for some of the gastrointestinal damage, particularly when large quantities of iron have been ingested, when the iron has been in contact with the mucosa for a prolonged time, and when the gastrointestinal lumen is otherwise empty.13'15 The anatomic location of the gastrointestinal damage is variable with proximal sectors more affected than distal ones.16·17 Because enteric-coated preparations tend to cause distal pathology,17 the ingestion of one of these formulations may result in the development of gastrointestinal effects later than if a standard preparation had been ingested. Other causes of the gastrointestinal damage include the formation of submucosal thrombi resulting in mucosal ischemia and necrosis.17
Some patients may experience a period of apparent recovery following the gastrointestinal effects. The occurrence of this asymptomatic or latent period can be confusing because the resolution of the gastroenteritis may be the first clinical sign of recovery in a mild case or may be only a temporary respite before generalized systemic toxicity develops in a more serious case. If this stage occurs, it is important that the patient be observed closely until it can be determined if the recovery is real or only transient. The cause of this latent period is unclear but it may be related to the time it takes for the absorbed iron to be distributed throughout the body and the time it takes for systemic damage caused by iron to become evident. In severe iron poisoning, this asymptomatic phase may not occur.
Figure 3. Mortality trends in children <6 years (iron-related deaths/exposures to iron supplements + adult vitamins with iron).
Systemic toxicity is characterized by multisystem damage, primarily in the forms of hepatotoxicity, metabolic acidosis, coagulopathies, and cardiovascular collapse. Hepatotoxicity is manifested by elevated serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and bilirubin. Periportal hepatic necrosis may occur in severe cases. Metabolic acidosis (with or without acidemia) is associated with an increased anion gap; tissue hypoperfusion leading to anaerobic metabolism and lipid peroxidation of hepatic mitochondrial membranes18 are the likely causes. Unsubstantiated hypotheses for the causes of metabolic acidosis include the conversion of ferrous iron to ferric iron, iron-related reduction in ATP generation leading to anaerobic metabolism, and iron-induced damage to the Krebs cycle leading to citric and lactic acidemia.
Coagulopathies, characterized by prolonged prothrombin time (PT) and partial thromboplastin time (PTT)1 may occur early (<8 hours) or be delayed (>24 hours).19 The early form of coagulopathy appears to be related to the plasma concentration of ferric iron and can be corrected by administering deferoxamine.19 The addition of free ferric iron to human plasma results in a reversible inhibition of thrombin's clotting effect on fibrinogen and reduction in thrombin generation, probably by impairing serine protease.20 The delayed form of coagulopathy is secondary to iron-induced hepatotoxicity and is characterized by reductions in the levels of clotting factors V, VH, IX, X, and fibrinogen.19
Age Distribution of Exposure to Medicinal Iron
Cardiovascular collapse (hypotension leading to shock) has been reported to occur early (within the first 6 to 8 hours) or late (24 to 36 hours after the overdose). In the early phase, shock is due to hypovolemia caused by gastrointestinal fluid loss. The fact that cardiovascular collapse may occur experimentally without gastrointestinal damage suggests that other mechanisms also play a role. Other findings in acute iron poisoning include tachycardia followed by bradycardia and decreased cardiac output with increased central venous pressure. Experimental data confirms that acute iron poisoning causes decreases in cardiac output, mean arterial pressure, and heart rate.21 Ironinduced myocarditis recently has been proposed to be a cause of decreased myocardial contractility; this mechanism has support from both the clinical and experimental sides. The clinically documented ironinduced myocardial damage postulated to be related to lipid peroxidation of myocyte organelle membranes due to iron-catalyzed free radical generation22 is supported by experimental data demonstrating ironinduced arrhythmias and loss of cell membrane integrity associated with delayed myocyte lipid peroxidation from high concentrations of iron.23
Hepatic cirrhosis and gastrointestinal obstruction from gastric or pyloric scarring occur rarely, even in severe cases.
The goals of the initial investigation of a patient who has ingested iron are to document the clinical status and to identify the need for chelation therapy. Clinical investigation should attempt to document the presence or absence of gastrointestinal and systemic damage. Due to the limited availability of emergency serum iron levels, several ancillary methods have been proposed to help identify which patients might need chelation therapy; unfortunately, not all of them give useful information.
A white blood cell count >15,000/mm3 and a serum glucose level >150 mg/dL have been claimed to correlate with serum iron levels >300 µg/dL,24 but recent studies have questioned the predictive value of these clinical laboratory tests25,26 and they are not widely used.
Mortality In <6 Years Age Group (1984 to 1993)
Serum iron levels generally are believed to be the best indicator of the severity of the poisoning. However, accurate interpretation of a serum iron level requires knowledge of the absorption and distribution kinetics of iron in overdose, and how these correlate with clinical severity. Unfortunately, little is known about the absorption rate of iron in overdose, the timing of peak serum iron levels, or the rate at which serum iron levels fall from their peak values. Further interpretation difficulties may arise if a controlled-release iron preparation has been ingested. One of the problems is that data from volunteer studies cannot be applied to the overdose situation because the absorption of small doses of iron is controlled by intestinal wall mechanisms. In an overdose, this protective mechanism is overwhelmed and iron absorption occurs rapidly. In fact, following overdoses, serum iron levels of 6798 ^gIdL and 16,706 µ?/dL have been measured at 90 to 120 minutes and 5 hours postingestion, respectively.27,28 Table 5 demonstrates an association of serum iron levels and clinical severity following overdoses with standard formulations of iron.29 In general, serum iron levels >500 µg/dL, whenever they are measured, are associated with serious systemic toxicjty 25
Classical teaching has been that a patient with a serum iron level above the total iron-binding capacity is at risk for developing systemic toxicity because there would be free unbound iron in circulation13 and it is only the free iron that distributes into the tissues to cause systemic toxicity. However, due to the method by which the total iron-binding capacity is determined in the laboratory, exposure to large amounts of iron or to deferoxamine will be associated with an elevation in the measured iron-binding capacity.11,25,30 For this reason, a measured iron-binding capacity above the serum iron level does not preclude the development of significant iron toxicity.
Plain radiographs of the abdomen may identify radiopaque iron tablets. A positive radiograph, one in which densely radiopaque tablets or particles can be identified, indicates that not all the ingested iron has been absorbed. The therapeutic implications of a positive radiograph of the abdomen are that gastrointestinal decontamination efforts have not been successful and that serum iron levels can be expected to rise. A negative radiograph (no radiopaque tablets or particles) means either that no iron was ingested or that the ingested iron tablets have dissolved (iron in solution is not radiopaque).31
Elemental Iron In Iron Complexes
Provocative chelation is another method that attempts to identify the presence of free unbound iron in the plasma. This technique consists of the administration of a single dose of deferoxamine which, if free unbound iron is available, will be excreted in the urine as the ferrioxamine complex (deferoxamine + iron). The presence of ferrioxamine in the urine is supposed to change the urine to a reddish or vin rose color, and the presence of the color change indicates the need for continued chelation therapy. A significant limitation to this approach is that the urine does not reliably change color even when elevated serum iron levels are present.25
The first step in treating a case of acute iron overdose is to provide appropriate supportive care with particular attention paid to fluid balance and cardiovascular stabilization. In a patient with a serum iron level <500 pg/dL, a conservative, supportive-care approach alone has resulted in good clinical outcomes.26
Initial treatment also should address the issue of preventing further absorption of iron from the gastrointestinal tract. Ipecac-induced emesis often is recommended within 2 hours of ingestion if the patient has had no spontaneous vomiting or diarrhea, despite the fact that there are no empirical data demonstrating an improved clinical outcome following its use. Because iron tablets are relatively large and become sticky in gastric fluid, gastric lavage is unlikely to be of benefit and its use is not recommended. The administration of activated charcoal is not recommended because iron is not adsorbed to it. Intragastric administration of either a bicarbonate or a phosphate solution has been demonstrated to be ineffective in preventing the gastrointestinal absorption of iron.32 Similarly, the oral administration of deferoxamine solution is not recommended because massive quantities would be needed and its efficacy in preventing iron absorption is uncertain.27 Cathartics (saline or sorbitol) and whole-bowel irrigation33 have been used to speed the passage of undissolved iron tablets through the intestinal tract. Occasionally, masses of undissolved iron tablets will adhere to the gastrointestinal wall and may need to be removal surgically.33
Classical Stages of Acute Oral Iron Poisoning
Deferoxamine is the iron-chelating agent of choice. Deferoxamine chelates or 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. The indications for using deferoxamine should be based on both clinical and laboratory parameters. Patients who have significant symptoms (eg, gastroenteritis, metabolic acidosis, early-onset coagulopathy, cardiovascular effects, or coma) and who have serum iron levels >350 µg/dL should be treated with intravenous deferoxamine although supportive care alone has been successful when serum iron levels are higher.26 When a serum iron level is not available, chelation should be initiated when significant symptoms are present.
Deferoxamine may be administered either intramuscularly or intravenously. The intramuscular route is not recommended because it is painful and less iron is excreted compared with the intravenous route of administration. The intravenous route is preferred, and the standard dose of deferoxamine is 15 mg/kg/hour as a continuous infusion. Patients with severe iron poisoning may require higher than normal infusion rates; in these cases, it is recommended that a regional poison center or medical toxicologist be contacted for guidance. There is no clear end-point of therapy but a practical approach is that the duration of therapy should depend on the severity of the poisoning. For moderate toxicity, deferoxamine should be administered for 8 to 12 hours while severe toxicity should be treated for 24 hours. Because these end-points are somewhat arbitrary and imprecise, the patient should be evaluated for the recurrence of toxicity (eg, hypotension or metabolic acidosis) 2 to 3 hours after the deferoxamine has been stopped. If deferoxamine treatment is required for more than 24 hours, it may be necessary to reduce the infusion rate.34,35
Serum Iron Levels and Clinical Severity
Adverse effects from using deferoxamine to treat acute iron poisoning are unusual.36 Excessive intravenous doses of deferoxamine (>15 mg/kg/hour) have been reported to be associated with the development of hypotension but the causal relationship and the clinical significance are unclear. Pulmonary toxicity (ARDS and tachypnea) has been described following prolonged deferoxamine treatment.35 Ocular and renal toxicities have been described only in patients with thalassemia or renal failure.
Continuous arteriovenous hemofiltration removes deferoxamine and the ferrioxamine complex but not free iron. Because it is uncertain how much total iron is removed by continuous arteriovenous hemofiltration, its clinical role has not been established. Hemodialysis and hemoperfusion have not been evaluated in acute iron poisoning.
The acute ingestion of medicinal iron preparations may result in serious poisoning, particularly in young children. The principle products involved are adult iron preparations, with or without vitamins. Although a single value for the toxic dose has not been established, significant gastrointestinal manifestations occur following the ingestion of 20 mg of elemental iron per kilogram of body weight while systemic toxicity may occur following the ingestion of at least 60 mg of elemental iron per kilogram of body weight. Treatment consists of stabilizing vital functions, removing unabsorbed iron from the gastrointestinal tract, and administering intravenous deferoxamine when there are serious clinical symptoms or when a serum iron level >500 µg/dL is measured within 8 hours of the ingestion. Optimal management, with the involvement of a medical toxicologist or a regional poison control center, often results in a favorable outcome.
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Age Distribution of Exposure to Medicinal Iron
Mortality In <6 Years Age Group (1984 to 1993)
Elemental Iron In Iron Complexes
Classical Stages of Acute Oral Iron Poisoning
Serum Iron Levels and Clinical Severity