As with any serious ingestion, initial stabilization must include supplemental oxygen, airway assessment, and establishment of IV access. Evidence of hematemesis or lethargy after an iron exposure may be a manifestation of significant toxicity. Intravenous volume repletion should begin while orogastric lavage and whole bowel irrigation (WBI) are considered. In any lethargic patient who likely will deteriorate further, early endotracheal intubation may facilitate safe GI decontamination measures. Abdominal radiography may be used to estimate the iron burden in the GI tract given the caveats discussed earlier. Laboratory values, including chemistries, hemoglobin, iron concentration, coagulation, and hepatic profiles, are necessary in the sickest patients. An arterial or venous blood gas or a lactate concentration rapidly identifies a metabolic acidosis. Patients who appear well and had only one or two brief episodes of vomiting can be observed pending discharge. A serum iron concentration and most other laboratory testing are not needed in patients who have minimal symptoms and normal vital signs.
GI decontamination procedures should be initiated after stabilization. Adequate gastric emptying is critical after ingestion of xenobiotics, such as iron, that are not well adsorbed to activated charcoal. Because vomiting is a prominent early symptom in patients with significant toxicity, induced emesis is not recommended. Orogastric lavage is more effective but may be of only limited value because of the large size and poor solubility of most iron tablets, their ability to form adherent masses,25,90 and their movement into the bowel several hours after ingestion.43 The presence and location of radiopaque tablets on abdominal radiography can help guide orogastric lavage. Orogastric lavage will likely not be successful after iron tablets move past the pylorus, so WBI may be more effective (Fig. 46–1).
A 17 month-old boy presented to the hospital with lethargy and hematemesis after a large ingestion of iron supplement tablets. Despite orogastric lavage and whole-bowel irrigation, iron tablets and fragments can be visualized in the stomach 4 hours after ingestion.
The same 17 month-old child 10 hours after ingestion. Persistent iron pills were removed from the stomach by gastrotomy. No further radiopaque fragments can be visualized; however, ARDS is now visible.
Many strategies were used in the past in attempts to improve the efficacy of orogastric lavage. At the present time, no data support the use of oral deferoxamine,32,40,98,99,104 bicarbonate,15,16 phosphosoda,4,27 or magnesium.13,75,93 Although some of these techniques demonstrate efficacy, avoidance of the associated risks mandates using only 0.9% sodium chloride solution or tap water for orogastric lavage.
The value of WBI in patients with iron poisoning is supported primarily by case reports and one uncontrolled case series.18,43, 82,83 However, the rationale for WBI use is logical, especially considering the limitations of other gastric decontamination modalities. The usual dose of WBI with polyethylene glycol electrolyte lavage solution (PEG-ELS) is 500 mL/h in children and 2 L/h in adults. This rate is best achieved by starting slowly and increasing as tolerated, often using a nasogastric tube and an infusion pump to administer large volumes. Antiemetics may be used to treat nausea and vomiting. A large volume (44 L) of WBI was administered safely over a 5-day period to a child who had persistent iron tablets on serial abdominal radiographs43 (Antidotes in Depth: A2 and Chap. 8).
For patients with life-threatening toxicity who demonstrate persistent iron in the GI tract despite orogastric lavage and WBI, upper endoscopy or gastrotomy and surgical removal of iron tablets adherent to the gastric mucosa may be necessary and lifesaving.25,66,90
Deferoxamine has been available since the 1960s as a specific chelator for patients with acute iron overdose or chronic iron overload (eg, multiple transfusions). Deferoxamine, which is derived from culture of Streptomyces pilosus, has high affinity and specificity for iron. In the presence of ferric iron (Fe3+), deferoxamine forms the complex ferrioxamine, which is excreted by the kidneys,44 usually imparting a reddish-brown color to the urine (Fig. 46–2). Deferoxamine chelates free iron and the iron transported between transferrin and ferritin51,67 but not the iron present in transferrin, hemoglobin, hemosiderin, or ferritin.5,44 Deferoxamine may work by other mechanisms in addition to binding excess systemic iron. Because 100 mg of deferoxamine chelates approximately 8.5 mg of ferric iron, recommended or typical therapeutic dosing of deferoxamine does not produce significant excretion of chelated iron in the urine, yet it does often result in dramatic clinical benefits (Antidotes in Depth: A7). Sufficient evidence suggests that deferoxamine can reach intracytoplasmic and mitochondrial free iron, thereby limiting intracellular iron toxicity.51
These timed sequential urines were obtained from a small child with a serum iron concentration of 990 µg/dL who was treated with intravenous deferoxamine. The characteristic color change is illustrated.
(Used with permission of The New York City Poison Center Toxicology Fellowship Program.)
IV administration of deferoxamine should be considered in iron-poisoned patients with any of the following findings: metabolic acidosis, repetitive vomiting, toxic appearance, lethargy, hypotension, or signs of shock. Deferoxamine administration is indicated for any patient with an iron concentration above 500 µg/dL. In patients manifesting serious signs and symptoms of iron poisoning, deferoxamine should be initiated as an IV infusion, starting slowly and gradually increasing to a dose of 15 mg/kg/h. Hypotension is the rate-limiting factor as more rapid infusions are used.38,96,98 Patients who appear toxic or have serum iron concentrations above 500 µg/dL should be treated with IV deferoxamine. Patients who have concentrations below 500 µg/dL and who do not appear toxic should be treated supportively without administration of parenteral deferoxamine (Fig. 46–3).
Algorithm for decision analysis following iron salt ingestion.
Clinicians have attempted to define the earliest clear end points for deferoxamine therapy because of possible deferoxamine toxicity. In one report, a urine iron-to-creatinine ratio (UI/Cr) was used to determine if free iron excretion into the urine continued during deferoxamine therapy.103 This ratio is a more objective measure of the presence of ferrioxamine in the urine than the less reliable and more subjective use of urinary color change.17,47,92 This method must be further studied clinically before its use can be advocated. Most authors agree that deferoxamine therapy should be discontinued when the patient appears clinically well, the anion-gap acidosis has resolved, and urine color undergoes no further change.55 In patients with persistent signs and symptoms of serious toxicity after 24 hours of IV deferoxamine, continuing therapy should be undertaken cautiously, if at all, and perhaps at a lower dose due to the risk of adverse events (Antidotes in Depth: A7).
Most adverse effects of deferoxamine are reported in the setting of chronic administration for the treatment of hemochromatosis.39,63,74 The same effects, such as acute respiratory distress syndrome (ARDS), are also described after treatment for acute iron overdose.84 Four patients with serum iron concentrations ranging from 430 to 620 µg/dL developed ARDS after IV administration of deferoxamine for 32 to 72 hours.84 An animal study revealed significantly increased pulmonary toxicity when high-dose deferoxamine therapy was administered in the presence of high concentrations of oxygen (75%–80% FiO2).1 The authors suggested that this effect was mediated via an oxygen free radical mechanism (Antidotes in Depth: A7).
Deferasirox is an oral iron chelator approved by the FDA for the treatment of chronic iron overload that was studied as a potential iron antidote in human volunteers following supratherapeutic iron ingestion. In a randomized, double blind, placebo-controlled study, volunteers were administered 5 mg/kg iron followed by deferasirox or placebo.34 Deferasirox resulted in lower iron concentrations in the treated group. However, concerns included the possibility that deferasirox may increase the absorption of iron complex and that the deferasirox dosing may need to be too high in patients with large exposures to effect these results. Further study is warranted before this therapy can be considered.
Many patients who ingest iron do not develop significant toxic effects. Recommendations for hospital referral of toddlers who ingest iron range from those with potential exposures of 20 mg/kg up to 60 mg/kg.6,47 These wide ranges probably result from the interpretation of retrospective studies in possibly “exposed” toddlers for whom the actual doses were estimated. Many authors suggest that doses were overestimated in patients who subsequently did not develop toxicity (Chap. 136). If a toddler remains asymptomatic or develops minimal or no GI manifestations after a 6 hour observation period in the emergency department, then discharge to an appropriate home situation can be considered. Patients who develop GI symptoms and signs of mild poisoning including vomiting and diarrhea can be observed as inpatients outside the intensive care unit. Patients who manifest signs and symptoms of significant iron poisoning, such as metabolic acidosis, hemodynamic instability, or lethargy, should be monitored and treated in an intensive care unit. Except in the case of carbonyl iron, hospital evaluation is recommended for any child with an estimated unintentional ingestion of more than 20 mg/kg of elemental iron. Children who appear well with unintentional ingestions between 10 and 20 mg/kg elemental iron and fewer than two episodes of vomiting should be closely followed at home in consultation with the poison control center.
The frequent diagnosis of iron deficiency anemia during pregnancy has led to serious and even fatal iron ingestions in pregnant women.8,45,62,69,88 In all cases of toxic exposures during pregnancy, maternal resuscitation should always be the primary objective, even if an antidote poses a real or theoretical risk to the fetus. Unproven concerns regarding possible deferoxamine toxicity to the fetus have inappropriately, and at times, disastrously delayed therapy.62,79 These fears about fetal deferoxamine toxicity are not supported in either human or animal studies,14,53,89 which have demonstrated that neither iron nor deferoxamine is transferred to the fetus in appreciable quantities. An animal study demonstrated that fetal serum iron concentrations were not elevated and fetal deferoxamine concentrations could not be detected in pregnant near-term ewes poisoned with iron and treated with deferoxamine. Fetal demise under these circumstances presumably results from maternal iron toxicity and not from direct iron toxicity to the fetus. Thus, deferoxamine should be used to treat serious maternal iron poisoning and should never be withheld because of unfounded concern for fetal exposure to deferoxamine.
Another modality used experimentally for treatment of iron intoxication is continuous arteriovenous hemofiltration (Chap. 10). In a study of five iron poisoned dogs, increased elimination of ferrioxamine in the ultrafiltrate was demonstrated when increasing doses of deferoxamine were infused into the arterial side of the system.7 A variant of this approach was utilized successfully in an iron poisoned toddler, who was treated with deferoxamine and venovenous hemofiltration.56 Although the authors demonstrated a decreasing serum iron concentration, only a minimal concentration of iron was measured in the ultrafiltrate. This was presumed secondary to the large volumes of infusate used. Theoretically, ferrioxamine in the blood could be dialyzable with new high molecular-weight (large-pore) dialysis filters, but this technique has not been studied.
In toddlers with severe poisoning, exchange transfusion may help to physically remove free iron from the blood while replacing it with normal blood. Exchange transfusion in children is effective for poisonings such as aspirin or theophylline when the volume of xenobiotic distribution is small and removal from the blood compartment can be expected. Treatment with exchange transfusion has been suggested in iron poisoning based on early reports and more recently reported in the successful treatment of an 18 month-old child with iron poisoning.10 However, removal of blood volume must be performed cautiously because it may not be well tolerated by iron poisoned patients with hemodynamic instability.