Steven E. Aks
HIGH-YIELD FACTS
• Estimation of risk of iron poisoning is based upon conversion of the ingested iron salt to elemental iron with >60 mg/kg being associated with significant toxicity.
• Phase II of iron poisoning is the quiescent phase. The patient appears improved, which may falsely reassure the clinician.
• Serum iron concentrations should be obtained between 4 and 6 hours after ingestion.
• Whole bowel irrigation (WBI) should be considered if multiple radiopaque iron tablets are seen on abdominal radiography.
• The preferred route of deferoxamine administration is intravenously at a rate of 15 mg/kg/h.
Iron is one of the most important poisons in children. It has a high potential for morbidity and mortality. According to data from the American Association of Poison Control Centers (AAPCC), from 1983 to 1990 iron was the most common cause of pediatric unintentional ingestion death, accounting for 30.2% of reported cases.1 From 1985 to 1989, there were more than 11,000 reported exposures to iron in children.
The FDA has required unit dose packaging (blister-packs) for products containing more than 30-mg elemental iron per tablet. After this change in packaging the rate of serious iron ingestions reported has plummeted.2 Despite the repealing of this regulation2 this positive outcome has persisted. In 2011 according to the National Poison Data System of the AAPCC there were a total of 3777 iron and iron salt ingestions. There were six cases with a major effect, but no deaths.3
PATHOPHYSIOLOGY
Iron is absorbed through the gastrointestinal mucosa in the ferrous (Fe2+) state. It is oxidized to the ferric (Fe3+) state and is bound to transferrin. Toxicity occurs when the transferrin-binding capacity is exceeded. Iron is a potent catalyst of free radical generation, which is the chief mechanism of iron toxicity. Circulating nontransferrin bound iron can damage blood vessels and can cause transudation of fluids from the intravascular space, resulting in hypotension. Hypotension is potentiated by the release of ferritin, a potent vasodilator. Other target organs include the gastrointestinal tract, the liver, and the cardiovascular system. Autopsy findings include cloudy swelling, fatty degeneration, and necrosis of hepatocytes. Iron deposits can be found in hepatocytes and the reticuloendothelial cells of the liver and spleen.
TOXICITY AND ESTIMATING RISK
It is important to identify the specific preparation because the content of elemental iron varies (Table 120-1). If the preparation and the number of tablets are known, the total dose of elemental iron can be calculated. A dose exceeding 60 mg of elemental iron per kilogram of body weight is associated with significant toxicity.
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TABLE 120-1 |
Iron Preparations |
CLINICAL PRESENTATION
Virtually all iron-poisoned patients have early gastrointestinal symptoms. This may be the only manifestation; however, more serious cases progress through five stages. These stages are sequential although there can be overlap. Not all iron-poisoned patients exhibit all five stages.
STAGE 1
This stage begins shortly after ingestion and lasts for about 6 hours. Mild cases demonstrate nausea and vomiting. More severe ingestions suffer vomiting, diarrhea, hematemesis, hypotension, and altered mental status. The latter two signs are manifestations of intravascular volume loss due to gastrointestinal hemorrhage.
STAGE 2
Stage 2 occurs from about 6 to 12 hours after ingestion and is referred to as the quiescent phase because the patient can appear to be improving, or may even be asymptomatic. A meticulous assessment for intravascular fluid loss is key to differentiating a patient in stage 2 from a patient who has recovered from a mild case of iron poisoning. A blood gas at this time may reveal a mild metabolic acidosis.
STAGE 3
This is the stage of cardiovascular toxicity, and it heralds the end of the quiescent stage. It may persist for 24 hours or longer. It is a distributive shock felt to be a consequence of fluid loss from the peripheral vasculature. Patients may develop altered mental status ranging from lethargy to coma. Previous gastrointestinal blood loss aggravates the shock. These patients develop a severe metabolic acidosis. Although hypoperfusion is a contributor, it is mostly a consequence of the hydration of non–transferrin-bound iron by the reaction Fe3+ + 3H2O → FeOH3 + 3H+. Thus, one ferric ion generates three protons. In serious cases the etiology of the shock becomes myocardial dysfunction (pump failure).4 This is typically fatal.
STAGE 4
This is the stage of hepatotoxicity. It usually occurs in the first 48 hours of a moderate-to-severe overdose. Transaminases greater than 2000 to 4000 are an ominous sign.5 After shock, hepatotoxicity is the second most common cause of death from iron poisoning.
STAGE 5
At 4 to 6 weeks after the ingestion, the patient may develop symptoms of a bowel obstruction. This is due to stricture development typically at the pylorus.
DIAGNOSIS
The most important laboratory tests to obtain are an abdominal x-ray, a serum iron concentration and measurement of the acid–base status. The x-ray is objective evidence that iron has been ingested and guides the need for gastrointestinal decontamination. The serum iron concentration predicts the potential for toxicity, and acidosis is evidence that it has occurred. Other important tests include electrolytes, renal and hepatic panels, and a coagulation profile. Iron poisoning is one of the conditions that can produce an anion-gap metabolic acidosis (see Chapter 112).
Iron levels should be obtained between 2 and 6 hours after ingestion but are optimally drawn at 4 hours postingestion. Levels greater than 500 μg/dL are typically associated with toxicity and levels greater than 1000 μg/dL are potentially fatal. Obtain serial levels every 2 to 4 hours until the iron level peaks.
TREATMENT
The preferred method of GI decontamination is whole bowel irrigation (WBI).6 Activated charcoal does not adsorb iron. WBI with polyethylene glycol electrolyte lavage solution (PEG-ELS) should be initiated if pills are seen on abdominal radiographs. PEG-ELS is given by nasogastric tube at a rate of 25 mL/kg/h in small children and 1 to 2 L/h in adolescents and adults. The end point of therapy is a clear rectal effluent. It is also useful to obtain a postirrigation abdominal x-ray to confirm the absence of pills. Active gastrointestinal bleeding, ileus, and bowel obstruction are contraindications to WBI.6
Even moderately poisoned children require meticulous supportive care to ensure a positive outcome. For patients in shock, large volumes of IV fluids and sodium bicarbonate are required to maintain fluid, electrolyte, and acid–base status.
Chelation with intravenous deferoxamine is used for significant iron ingestions. Indications are the presence of significant symptoms or signs of iron poisoning, a serum iron concentration greater than 500 μg/dL or metabolic acidosis.
Deferoxamine should be administered at a rate of 15 mg/kg/h. Administration of intravenous deferoxamine to patients with intravascular volume deficits risks nephrotoxicity. It is important to provide a bolus of crystalloid before initiating the deferoxamine infusion. The duration of chelation therapy is variable; there are no reliable end points.7 Serum iron determinations during the course of iron poisoning do not reflect clinical toxicity, and they are often unreliable during deferoxamine therapy.
Using a return of urine color to normal is not recommended as an end point for chelation therapy. It has never been validated, and pigmentation of urine (vin rose urine) is concentration and pH dependent. The most useful criterion for continued chelation is the presence of a metabolic acidosis despite satisfactory perfusion. This indicates the presence of non–transferrin-bound iron in the plasma. Deferoxamine is rarely required beyond the initial 24 hours after iron ingestion.
Hypotension is a potential side effect of intravenous deferoxamine therapy if it is given too rapidly. In a dog model, hypotension has been observed at infusion rates of 100 mg/kg/h. It is not reported at the usually recommended rate in humans, 15 mg/kg/h. Delayed pulmonary toxicity with symptoms resembling those of acute respiratory distress syndrome has been reported in patients who received prolonged chelation (>24 hours).8
Renal failure can be seen in ill hypovolemic patients. For patients undergoing chronic therapy, visual and hearing deficits and Yersinia infections have been reported.
DISPOSITION
Children with peak serum iron levels less than 500 μg/dL approximately 4 hours after ingestion and without symptoms of toxicity may be discharged in the care of reliable caretakers. Children treated with deferoxamine should be admitted to hospital. Those with metabolic acidosis, hypotension, or shock should be admitted to an intensive care unit. Patients who have ingested iron as a suicidal gesture require a mental health evaluation prior to discharge from the emergency department.
REFERENCES
1. Litovitz TL, Manoguerra A. Comparison of pediatric poisoning hazards: an analysis of 3.8 million exposure incidents: a report from the American Association of Poison Control Centers. Pediatrics. 1992; 89:999–1006.
2. Tenenbein M. Unit-dose packaging of iron supplements and reduction of iron poisoning in young children. Arch Pediatr Adolesc Med. 2005;159:557–560.
3. Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC. 2011 Annual Report of the American Association of PoisonControl Centers’ National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol (Phila). 2012;50:911–1164.
4. Tenenbein M, Kopelow ML, deSa DJ. Myocardial failure and shock in iron poisoning. Human Toxicol. 1988;7:281–284.
5. Tenenbein M. Hepatotoxicity in acute iron poisoning. J Toxicol Clin Toxicol. 2001;39:721–726.
6. American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position paper: whole bowel irrigation. J Toxicol Clin Toxicol. 2004;42:843–854.
7. Tenenbein M. Benefits of parenteral deferoxamine for acute iron poisoning. J Toxicol Clin Toxicol. 1996;34:485–489.
8. Tenenbein M, Kowalski S, Sienko A, Bowden DH, Adamson IY. Pulmonary toxic effects of continuous desferrioxamine administration in acute iron poisoning. Lancet. 1992;339:699–701.