Deferoxamine

Deferoxamine is a specific chelating agent derived from Streptomyces pilosus and has been used to treat iron toxicity since the 1960s. Deferoxamine binds directly to free iron and indirectly to iron from ferritin, hemosiderin, and non-protein-bound ferric salts, as well as to intracytoplasmic and mitochondrial free iron to form the complex ferrioxamine, which is renally excreted. It is safely administered to children and pregnant women. Complete complexation of ingested iron is not the goal of therapy. Indeed, only a small fraction of the total amount of ingested iron is found in the urine following chelation. Deferoxamine administration may be a clinically effective treatment by removing a critical amount of intracellular iron from its target, restoring cellular function.

Deferoxamine can be administered by various routes. Oral deferoxamine is not recommended due to the risk of increased GI absorption of iron-deferoxamine complex and enhanced toxicity. Deferoxamine may be administered subcutaneously but only in cases of chronic iron overload. Patients with mild iron toxicity from an acute ingestion may be treated with intramuscular (IM) administration of deferoxamine 90 mg/kg up to 1 g in children and 2 g in adults. The dose may be repeated every 4 to 6 h as clinically indicated (see below). This route of administration, however, can become difficult due to the volume of injected material required when used in children.

In patients with severe iron poisoning, fluid loss and hypovolemia may become significant. Since these patients require aggressive fluid resuscitation and since more consistent absorption of deferoxamine is achieved parenterally, therapy should be given IV, because this addresses both issues at once. Additionally, IM deferoxamine is not reliably absorbed in hypotensive patients. Hypotension is the rate-limiting factor in IV administration, and it is recommended to begin the infusion slowly (5 mg/kg/h). A second IV access will likely be required so as not to impede simple volume resuscitation. Deferoxamine can be increased to 15 mg/kg/h within the first hour of treatment, as tolerated. In fact, much higher doses have been used safely to achieve appropriate chelant excess before systemic toxicity occurred. However, it is generally not recommended to exceed a total daily dose of 6 to 8 g, although there are no specific data supporting this limit in acutely iron-poisoned patients. Administering deferoxamine at this rate will achieve a total of 6 g in about 6 h in an average-sized adult. Once this amount is reached, it is prudent to decrease the rate of deferoxamine administration, because of several associated risks. Adverse effects may include mucormycosis infection, 12 renal insufficiency,13 pulmonary toxicity,14 and sepsis from Yersinia enterocolitica, which may be related to duration of therapy.

The determination of the efficacy and duration of deferoxamine therapy involves acquisition of serial urine samples. As ferrioxamine is excreted, the urine color changes to what is classically called vin rosé but may actually appear brown or rusty. Theoretically, the disappearance of the vin rosé means that a patient no longer has a significant toxicity. It is important to obtain a urine sample prior to initiating treatment, because patients who are hypovolemic will likely produce concentrated urine, which may also be somewhat dark and may be confused with the vin rosé appearance. False negatives, color-change latency, and difficulty visualizing a color change can limit the utility of this test.

There is some controversy surrounding how long deferoxamine therapy should continue. Recommended end points range from clinical recovery and normal iron levels, to measurement of iron-to-creatinine ratios,15 to clinical recovery with normal iron level in conjunction with normal urine color. 4 Since measured iron levels are artificially depressed by the presence of deferoxamine and urine color change can be unreliable, and since iron toxicity is a clinical diagnosis, clinical recovery of the patient is probably the most important factor in terminating therapy. For patients who continue to exhibit severe iron toxicity after 24 h of deferoxamine therapy, the therapy should continue carefully at a decreased dose, for reasons mentioned earlier.

Previously advocated was the deferoxamine challenge test, a half-dose of 50-mg/kg IM injection of deferoxamine followed by examination of urine samples for change in color that would indicate the presence of chelated free iron and therefore confirm iron toxicity. More recently, a first dose of 90 mg/kg IM has been used, also utilizing change in urine color to verify toxicity. There may be several problems with this management strategy. Single-dose deferoxamine can be unreliable in eliciting a visible color change in urine, especially if a pre-deferoxamine urine sample was not obtained, and should not be the sole factor in deciding toxicity. 4 Additionally, IM therapy does not address the issue of fluid resuscitation, which these patients very frequently require even if they do not require the antidote.

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