Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) ANCOR EN 80
2) ANCOR EN 80/150
3) ARMCO IRON
4) EFV 250/400
5) EO 5A
6) FERROVAC E
7) FERRUM
8) GS 6
9) IRON
10) IRON, ELECTROLYTIC
11) IRON, ELEMENTAL
12) IRON, POWDERED
13) IRON, REDUCED (FCC)
14) LOHA
15) NC 100
16) PZH-1M3
17) PZH-2
18) PZH1M1
19) PZH2M1
20) PZH2M2
21) PZH3
22) PZH3M
23) PZH4M
24) PZh2M
25) PZhO
26) REMKO
27) SUY-B 2
28) 3ZhP
29) AMMONIUM IRON SULFATE
30) FERROUS
31) FERROUS ION
32) FERROUS METAL BORINGS, SHAVINGS, TURNINGS, OR CUTTINGS
33) IRON (FE 2+)
34) IRON (II) ION
35) IRON (III) CHLORIDE, SOLUTION
36) IRON OXIDE DUST AND FUME
37) IRON SESQUICHLORIDE
38) IRON(2+)
39) IRON, ION(FE 2+)
40) JEWELER'S ROUGE
41) NATURAL HEMATITE
42) VOGEL'S IRON RED
43) ZELAZA TLENKI (POLISH)

1.2.1) MOLECULAR FORMULA
1) FERRIC PYROPHOSPHATE CITRATE: Fe4(C6H4O7)3(H2P2O7)2(P2O7)
2) IRON: Fe
3) IRON SUCROSE: [Na2Fe5O8(OH).3H2O]n.m(C12H22O11)
4) SODIUM FERRIC GLUCONATE COMPLEX: [NaFe2O3(C6H11O7)(C12H22O11)5]n of approximately 200

Available Forms Sources

A)

1) INDUSTRIAL FORMS

a) Powdered iron is a gray lustrous substance (AAR, 1998; (HSDB , 1999).
b) Iron is a silver-white metal (Lewis, 1997; Clayton & Clayton, 1994; Lewis, 1996; HSDB , 1999).
c) Also available as crystals, whiskers, and iron sponge (Lewis, 1997).
d) Common valences are 2 and 3 (Budavari, 1996) Lewis, 1997), seldom 1, 4, 6 (Budavari, 1996; HSDB , 1999).
e) Four naturally occurring isotopes (Lewis, 1997; Budavari, 1996; HSDB , 1999):

1) 54 (5.82%)
2) 56 (91.66%)
3) 57 (2.19%)
4) 58 (0.33%)

f) Four artificial, radioactive isotopes (Lewis, 1997; Budavari, 1996):

1) 52
2) 53
3) 55
4) 59-61

g) Although iron occurs in pure form, it is more commonly found as oxide or carbonate (Clayton & Clayton, 1994; Lewis, 1998), or as sulfide or silicate (Clayton & Clayton, 1994).
h) Iron carbonyl (iron pentacarbonyl) equals 2.58% iron.

B)

1) Important source ores (Budavari, 1996; Harbison, 1998; HSDB , 1999; ILO, 1998; Lewis, 1997; Zenz, 1994):

1) hematite (Fe2O3)
2) magnetite (Fe3O4)
3) limonite ((FeO(OH)-nH2O)
4) siderite (FeCO3) (also taconite (Lewis, 1997))

2) Derivatives obtained during iron production include aniline, copper, ferric chloride, ferroboron, ferrocene, ferrosilicon, ferrous chloride, ferrovanadium and iron pentacarbonyl (Ashford, 1994).
3) INDUSTRIAL SOURCES

a) Powdered iron can be produced via:

1) Arc furnace reduction of ilmenite with metallurgic coke (Ashford, 1994).
2) Thermal decomposition of the yellow liquid iron pentacarbonyl Fe(CO)5 at 250 degrees C (Clayton & Clayton, 1994; Lewis, 1997), yielding dark-gray powder (Lewis, 1996).
3) Filter purification and vacuum crystallization of ferrous chloride solution (obtained from ore or scrap treatment with hydrochloric acid), followed by dehydration and reduction of ferrous chloride dehydrate powder at 800 degrees C (Lewis, 1997), yielding gray-black powder (Lewis, 1996).
4) Hydrogen-reduction of high-purity ferric oxide or oxalate (Lewis, 1997), yielding gray-black powder (Lewis, 1996).
5) Electrolytic deposition from solutions of a ferrous salt (Lewis, 1997), yielding lusterless, gray-black powder (Lewis, 1996).

b) Molten (or pig) iron can be produced via:

1) Blast furnace smelting of iron ore, metallurgic coke, and limestone (Ashford, 1994; Lewis, 1997).
2) In the U.S.: mainly from taconite (crude, low-grade iron ore, containing primarily hematite and silica) (Clayton & Clayton, 1994).
3) Continuous reduction of preheated iron ore and limestone in fluidized bed, heating to 926 degrees C, melting at 1926 degrees C, reduction of iron in the presence of coal at 1648 degrees C (Lewis, 1997).

4) DIETARY SOURCES

a) The required daily amount of iron of 10-20 mg for adults is supplied through average diet (Baselt & Cravey, 1995).
b) The average daily intake for adults is 15 mg (Clayton & Clayton, 1994).
c) In the United States, supplemental iron is contained in flour, some breakfast cereals and vitamin preparations (Baselt & Cravey, 1995).
d) EPA set the Federal Drinking Water Guidelines for iron at 300 mcg/L (HSDB , 1999).

5) ENVIRONMENTAL SOURCES

a) Iron is found in 5.1% of the earth's crust. It is the second most abundant metal (Budavari, 1996) and the fourth most abundant element (Clayton & Clayton, 1994).
b) The content in the earth's crust is 50,000 ppm (Clayton & Clayton, 1994).
c) It is believed that the earth's core consist mainly of iron (Budavari, 1996).
d) Native iron, found in Greenland, exists as small grains or nodules in basalt (HSDB , 1999).

C)

1) INDUSTRIAL/COMMERCIAL USES

a) Iron is primarily used in powder metallurgy and serves as a catalyst in chemical reactions (AAR, 1998).
b) Iron is a component of carbon steels, cast iron, high-speed steels, high-strength low-alloy steels, manganese alloy steels, and stainless steels (Ashford, 1994).
c) Steel is the most important alloy of iron. It contains 0.25-2% of carbon. Tensile strength increases with increase in carbon content (Clayton & Clayton, 1994).

1) Alloyed with carbon (C), manganese (Mn), chromium (Cr), nickel (Ni) and other elements, iron is used to form steel (Budavari, 1996; Sittig, 1991)

d) Wrought iron is almost pure iron (Clayton & Clayton, 1994).
e) Ignition of a mixture of iron and potassium perchlorate generates heat sufficient for metal welding (Urben, 1995).
f) Iron uses include magnets, dyes, pigments, abrasives, and polishing compounds such as jeweler's rouge (Harbison, 1998).
g) Iron is used to increase the density of fluids used in oil-well drilling (ILO, 1998).
h) HAND WARMER: Iron powder is used in hand warmers available worldwide, especially in Japan, Canada and the United States. The iron powder and other contents of the hand warmer (activated charcoal, salt and vermiculite) create an exothermic chemical reaction when exposed to air or moisture (Tam et al, 2008). One patient developed a "warm sensation" in her mouth and epigastrium after ingesting a piece of a hand warmer (Hot Hands 2) containing 5 to 8 grams of elemental iron. Laboratory results revealed a serum iron concentration of 235 mcg/dL obtained 6 hours postingestion. Some heat warmers may contain up to 60 g of iron powder (Weiland & Sherrow, 2015).

2) BIOLOGICAL/ENVIRONMENTAL USES

a) Iron is essential to life. It is a constituent of biological pigments such as hemoglobin, cytochromes and ferrichromes (Lewis, 1998).
b) Iron is believed to be essential for normal growth and nutrition of all living cells, including microorganisms (Baselt & Cravey, 1995; Dragun, 1988; Lewis, 1997).
c) Iron, one of the ten trace elements, is required in the diet of higher animals, including humans, and is the most abundant trace metal in the human body (Schardein, 1993; Baselt & Cravey, 1995).

1) RECOMMENDED DAILY INTAKE: Adults require 10-20 mg of elemental iron daily. This amount is supplied through average diet (Baselt & Cravey, 1995). During pregnancy, the daily requirement increases to 30 mg (TERIS , 1999).

3) Injections of iron dextran (complex of ferric hydroxide and dextran) are used to treat iron deficiency anemia in humans and piglets (Clayton & Clayton, 1994).
4) Iron isotopes 55Fe and 59Fe are used in tracer studies (Budavari, 1996).

a) 55Fe is used as a biological tracer (Budavari, 1996). Its half-life is 2.91 years (Lewis, 1997).
b) 59Fe (half-life 46.3 days) emits beta and gamma radiation. It is used in medicine and as a tracer element in biochemical and metallurgical research (Lewis, 1997).

5) Iron participates in cellular oxidative processes (Lewis, 1997). Iron ions are involved in various biological processes, such as oxygen transport, electron transport, and nitrogen fixation (Budavari, 1996; Zenz, 1994).
6) The body burden of a human, weighing 70 kg, is about 4.1 g (ranges 3-5 g) (Clayton & Clayton, 1994; Zenz, 1994).

a) Iron is a constituent of hemoglobin (Lewis, 1997). Hemoglobin contains about 67% of the body iron (Clayton & Clayton, 1994; Zenz, 1994).
b) About 27% (ranges 20-30%) of the body iron is stored in the liver as ferritin (physiological) or hemosiderin (pathological conditions) (Clayton & Clayton, 1994; Zenz, 1994).

7) Iron is essential for proper functioning of myoglobin, heme-containing enzymes, and metalloflavoprotein enzymes (Harbison, 1998).
8) Iron tablets, used to orally treat iron deficiency, contain soluble iron salts and are potentially toxic. Ingestion of 0.5 g of iron may result in vomiting, ulceration of the gastrointestinal mucosa, intestinal bleeding, and possibly liver and kidney damage (Zenz, 1994).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Found primarily as a nutritional supplement in vitamins. Used for the treatment and prevention of iron-deficiency anemia.
B) PHARMACOLOGY: Iron is required in the function of multiple essential protein and enzyme complexes including hemoglobin, myoglobin, and cytochromes.
C) TOXICOLOGY: Iron is a general cellular poison and is directly corrosive to the GI mucosa.
D) EPIDEMIOLOGY: Historically, a common poisoning which was one of the leading causes of pediatric toxicologic deaths. Exposure has been reduced in recent years with improved packaging, but still has the potential for significant morbidity and mortality.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: GI upset, constipation.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE POISONING: Vomiting and diarrhea may occur within 6 hours of ingestion.
2) SEVERE POISONING: Severe vomiting and diarrhea, lethargy, metabolic acidosis, shock, GI hemorrhage, coma, seizures, hepatotoxicity, and late onset GI strictures.
3) CLINICAL COURSE (May Not Occur In All Cases) includes the following:

a) PHASE I (0.5 to 2 hours) includes vomiting, hematemesis, abdominal pain, diarrhea, hematochezia, lethargy, shock, acidosis, and coagulopathy. Necrosis to the GI tract occurs from the direct effect of iron on GI mucosa. Severe gastrointestinal hemorrhagic necrosis with large losses of fluid and blood contribute to shock.
b) PHASE II includes apparent recovery; continue to observe patient closely.
c) PHASE III (2 to 12 hours after phase I) includes profound shock, severe acidosis, cyanosis, and fever. Increased total peripheral resistance, decreased plasma volume, hemoconcentration, decrease in total blood volume, hypotension, CNS depression, and metabolic acidosis have been demonstrated.
d) PHASE IV (2 to 4 days) includes possible hepatotoxicity. Thought to be a direct action of iron on mitochondria. Monitor liver function tests and bilirubin. Acute lung injury may also occur.
e) Phase V (days to weeks) includes GI scarring and strictures. GI obstruction secondary to gastric or pyloric scarring may occur due to corrosive effects of iron. Sustained-release preparations have resulted in small intestinal necrosis with resultant scarring and obstruction.

4) Carbonyl iron (also referred to as "iron carbonyl") appears to be less toxic than other iron formulations because of limited absorption. Please refer to the CARBONYL IRON management for further information.
5) Case reports suggest that iron-dextran complex overdoses may be associated with high serum iron concentrations without evidence of a corresponding degree of clinical symptoms and signs of toxicity. Please refer to the IRON DEXTRAN management for further information.

0.2.20)

A) Ferric citrate, iron sucrose, and the sodium ferric gluconate complex have been classified by the manufacturers as FDA pregnancy category B. Various iron salts are used therapeutically to correct iron deficiency in pregnancy. Iron-deficiency anemia has been associated with an increased risk of preterm delivery and low birth weight. There are no adequate or well-controlled studies of ferric pyrophosphate citrate use during pregnancy. Because ferric pyrophosphate citrate may cause fetal harm, advise female patients of reproductive potential to use effective contraception while using the drug and for at least 2 weeks after ending treatment. It is not known whether sodium ferric gluconate complex is excreted into human breast milk.
B) Case reports of pregnant women who have received early aggressive treatment (decontamination and/or deferoxamine) for iron overdose have described good fetal outcomes.

0.2.21)

A) At the time of this review, no human data were available to assess the potential carcinogenic activity of supplemental iron sucrose. Cases have linked gastric carcinoma with increased plasma ferritin levels and pulmonary, renal, and other cancers with exposure to iron workers in the metal industry.

Laboratory Monitoring

A)

B)

C)

D)

E)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Supportive care with intravenous fluid hydration is usually sufficient for mild poisonings. Activated charcoal is not effective for iron ingestions. Patients who are symptomatic should be observed for clinical deterioration and development of acidosis. Abdominal x-rays should be obtained as tablets are generally radiopaque. When large amounts of tablets are visible on radiograph, consider whole bowel irrigation. An iron concentration should be measured 4 to 6 hours after the initial ingestion and then repeated in 2 to 4 hours. Patients who develop metabolic acidosis or are clinically worsening with IV hydration should be treated with chelation.

B) MANAGEMENT OF SEVERE TOXICITY

1) Chelation with deferoxamine is needed for patients with signs of severe poisoning including shock, acidosis, GI hemorrhage, and lethargy or coma. Consider chelation for serum iron concentrations greater than 500 mcg/dL (a patient will usually have significant signs and symptoms of toxicity). Patients may need blood transfusions if they have significant GI hemorrhage.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal is not useful. Most patients have spontaneous vomiting.
2) HOSPITAL: Activated charcoal does not adequately bind iron and is not useful. Studies have suggested that magnesium hydroxide antacids (5 mg magnesium hydroxide per gram of elemental iron ingested) decrease serum iron concentrations following a simulated overdose. Gastric lavage may be useful soon after ingestion in adults, but the nasogastric tubes used in children are not sufficiently large to remove tablets. In patients with large amounts of radiopaque tablets in the GI tract, whole bowel irrigation with polyethylene glycol should be considered. Endoscopic removal is another option for patients with a large number of tablets in the stomach.

D) AIRWAY MANAGEMENT

1) Patients who are comatose or with altered mental status may need mechanical respiratory support and orotracheal intubation.

E) ANTIDOTE

1) DEFEROXAMINE can be used to chelate iron and should be used when there are signs of severe poisoning including shock, acidosis, GI hemorrhage, and coma. Deferoxamine is administered intravenously at a rate of 15 mg/kg/hour; it can be titrated up to a rate of 40 mg/kg/hour for patients with severe poisoning. However, hypotension may occur with high dose deferoxamine infusion and the rate should be slowed if this occurs. Deferoxamine should be continued for 12 to 24 hours and then titrated off if the patient is clinically improving. If the patient worsens as the deferoxamine is titrated off, it should be restarted. Prolonged (greater than 24 hours) high dose infusion of deferoxamine has been associated with acute lung injury and should be avoided. Patients receiving deferoxamine chelation are at increased risk for Yersinia enterocolitica sepsis.

F) SEIZURE

1) IV benzodiazepines, barbiturates as necessary.

G) HYPOTENSION

1) IV 0.9% NaCl, dopamine, norepinephrine as indicated.

H) ENHANCED ELIMINATION

1) Hemodialysis is not effective in removing iron, but may be necessary to remove deferoxamine-iron complexes in patients with renal insufficiency. Consider exchange transfusion in those patients with a serum iron exceeding 1000 mcg/dL who clinically deteriorate despite supportive care and intravenous chelation therapy.

I) PATIENT DISPOSITION

1) HOME CRITERIA: Inadvertent ingestions of less than 40 mg/kg of elemental iron in patients who have only mild GI symptoms (self limited vomiting or diarrhea) can be watched at home.
2) OBSERVATION CRITERIA: Patients with more than mild Symptoms, those who have ingested 40 mg/kg or more, or patients with intentional ingestions should be sent to a healthcare facility for evaluation.
3) ADMISSION CRITERIA: Patients who have hypotension, severe or worsening metabolic acidosis, GI hemorrhage, altered mental status, or require chelation should be admitted.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings and for recommendations on determining the need for chelation or whole bowel irrigation. Consult a gastroenterologist for endoscopic removal if many tablets persist in the stomach.

J) PITFALLS

1) Total iron binding capacity (TIBC) is unreliable in iron overdose. The elemental iron component is the iron dosage of interest and needs to be calculated for any given iron formulation. Prolonged (greater than 24 hours) high dose infusion of deferoxamine has been associated with acute lung injury and should be avoided.

K) PHARMACOKINETICS

1) Peak concentrations vary slightly depending on the formulations but generally occur by 6 hours in therapeutic dosing.

L) TOXICOKINETICS

1) Increased iron absorption occurs during overdose because of disruption of GI mucosa as well as increased passive absorption because of a larger concentration gradient.

M) DIFFERENTIAL DIAGNOSIS

1) The differential diagnosis of an acute iron ingestion is extremely broad and would include any process causing vomiting and abdominal pain. Hemorrhage may or may not be noted initially.

0.4.4)

A) Diagnosis of iron intraocular foreign body can be done by x-ray, by computerized tomography, by establishing that the foreign body can be moved with a magnet, and by electroretinogram. Magnetic resonance imaging is not recommended as movement of the foreign body may result.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) ADVERSE EFFECTS: GI upset, constipation.

F)

1) MILD TO MODERATE POISONING: Vomiting and diarrhea may occur within 6 hours of ingestion.
2) SEVERE POISONING: Severe vomiting and diarrhea, lethargy, metabolic acidosis, shock, GI hemorrhage, coma, seizures, hepatotoxicity, and late onset GI strictures.
3) CLINICAL COURSE (May Not Occur In All Cases) includes the following:

a) PHASE I (0.5 to 2 hours) includes vomiting, hematemesis, abdominal pain, diarrhea, hematochezia, lethargy, shock, acidosis, and coagulopathy. Necrosis to the GI tract occurs from the direct effect of iron on GI mucosa. Severe gastrointestinal hemorrhagic necrosis with large losses of fluid and blood contribute to shock.
b) PHASE II includes apparent recovery; continue to observe patient closely.
c) PHASE III (2 to 12 hours after phase I) includes profound shock, severe acidosis, cyanosis, and fever. Increased total peripheral resistance, decreased plasma volume, hemoconcentration, decrease in total blood volume, hypotension, CNS depression, and metabolic acidosis have been demonstrated.
d) PHASE IV (2 to 4 days) includes possible hepatotoxicity. Thought to be a direct action of iron on mitochondria. Monitor liver function tests and bilirubin. Acute lung injury may also occur.
e) Phase V (days to weeks) includes GI scarring and strictures. GI obstruction secondary to gastric or pyloric scarring may occur due to corrosive effects of iron. Sustained-release preparations have resulted in small intestinal necrosis with resultant scarring and obstruction.

4) Carbonyl iron (also referred to as "iron carbonyl") appears to be less toxic than other iron formulations because of limited absorption. Please refer to the CARBONYL IRON management for further information.
5) Case reports suggest that iron-dextran complex overdoses may be associated with high serum iron concentrations without evidence of a corresponding degree of clinical symptoms and signs of toxicity. Please refer to the IRON DEXTRAN management for further information.

Vital Signs

3.3.4)

A) WITH POISONING/EXPOSURE

1) Hypotension may develop after severe poisoning secondary to vomiting, diarrhea, blood loss, or vasodilation.

Heent

3.4.3)

A) Iron particles as foreign bodies in the cornea or sclera principally have local effects; whereas, if they are in the posterior part of the globe, in the vitreous humor, or in the vicinity of the lens, the effect may be widespread and serious (Grant & Schuman, 1993).

1) In the cornea, iron particles rapidly produces a rust ring (staining the immediately surrounding cornea the color of rust). This is often associated with irritation and discomfort, hyperemia of the conjunctiva, and presence of inflammatory cells in the anterior chamber. When iron enters the cornea from the anterior chamber, it is seen as brown rusty spots in the stroma and the iris becomes discolored (Grant & Schuman, 1993).
2) When an iron foreign body is located in the posterior segment of the eye, glaucoma and ocular siderosis have been reported. The glaucoma may be chronic. The cause of the glaucoma maybe the initial physical trauma, attempts of removal, or the siderosis itself (Grant & Schuman, 1993).
3) The vitreous body in the siderosis can become liquefied and contain floating opacities. It can also develop membranes and become contracted. Retinal detachment may result. Occult intraorbital or intraocular foreign body has been the cause of unilateral traumatic glaucoma (Grant & Schuman, 1993).
4) Ocular siderosis may cause retinal damage resulting in a gradual decrease in visual acuity ending ultimately in blindness. The time of onset varies greatly but may occur within months and can lead to blindness in 1 or 2 years (Grant & Schuman, 1993).
5) Siderosis of the iris commonly causes the pupil to be larger than normal, with poor reaction to light, accommodation, or atropine. The lens develops discoloration (cataractous with yellowish-brownish coloration) from a particle of iron embedded in the lens. Small round yellowish-brownish dots are arranged in a ring pattern under the anterior lens capsule (Grant & Schuman, 1993).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension may develop 2 to 6 hours after severe poisoning secondary to vomiting, diarrhea, blood loss or vasodilation.
b) CASE SERIES: Sixteen cases of ferric chloride poisoning between the years of 1990-2001 were analyzed, and hypotension was reported in 12.5% of patients (Wu et al, 2003).

B) HEART FAILURE

1) WITH POISONING/EXPOSURE

a) Cardiac failure has been reported on the second day following severe acute iron poisoning (Tenebein et al, 1988). Iron-mediated lipid peroxidation of myocite organelle membranes (Watts, 1999) and impairment of cardiac mitochondrial respiratory enzyme activity (Link, 1998) are the proposed mechanism. Cardiac toxicity is a well-known complication of chronic iron overload.

C) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) Risk of fatal myocardial infarction was over 2 fold higher in males, and over 5 fold higher in females, with serum iron levels of at least 175 mcg/dL (Morrison et al, 1994).

D) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Following the ingestion of 200 mL ferric chloride (equivalent to 11.52 grams or 230 mg/kg of elemental iron), a 25-year-old woman developed severe vomiting with metabolic acidosis and respiratory alkalosis. Death from cardiopulmonary arrest occurred within 4 hours of ingestion(Wu et al, 1998).

E) ELECTROCARDIOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) In another adult case, deeply inverted T waves in the precordial leads were described on the EKG; the patient recovered (Wallack & Winkelstein, 1974).

3.5.3)

A) ANIMAL STUDIES

1) CARDIAC FAILURE

a) DOGS with acute iron intoxication required aggressive fluid resuscitation to maintain intravascular volume. Cardiac output fell despite maintenance of preload and peripheral vascular resistance, probably secondary to decreased heart rate (Vernon et al, 1989).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Noncardiogenic pulmonary edema may develop in severe iron intoxication 12 hours to several days after ingestion (Tenenbein et al, 1988). Use of high doses of deferoxamine for longer than 24 hours may contribute to the development of noncardiogenic pulmonary edema.
b) CASE REPORT: A 17-year-old man, with an extreme iron level of 18,570 mcg/dL, developed acute lung injury with the findings of increased arterial-alveolar oxygen gradient and typical radiographic changes. Oxygenation and hemodynamic function deteriorated and the patient died approximately 8 hours after exposure despite aggressive treatment and supportive care (Perrone et al, 2000).

B) ADULT RESPIRATORY DISTRESS SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 47-year-old man who presented to the ED with signs of shock and coma, later developed renal failure, anion gap metabolic acidosis, acute respiratory distress syndrome (ARDS), and liver failure. His medication history showed that he had been using ferrous fumarate. Laboratory results revealed a serum iron concentration of 41 mcmol/L (10 to 30 mcmol/L) on admission. He was treated with desferrioxamine which decreased the serum iron concentration to 23 mcmol/L within 3 days; however, he developed massive gastrointestinal bleeding 4 weeks after presentation and he died despite receiving blood transfusions (Wolters et al, 2014).

C) PULMONARY ASPIRATION

1) WITH POISONING/EXPOSURE

a) Bronchial stenosis developed 4 months after aspiration of a 100 mg ferrous sulfate tablet in a 60-year-old woman (Tarkka et al, 1988).
b) Godden et al (1991) reported cough, chest pain, and bleeding caused by aspiration of a ferrous sulfate tablet. Mizuki et al (1989) reported another such case.
c) CASE REPORT: Because an iron pill can disintegrate in the airway unlike other foreign bodies, it may be difficult to detect on bronchoscopy. A 69-year-old woman developed recurrent episodes of pneumonia and inflammation 1 year after aspirating an iron pill. Although the pill was not detected on bronchoscopy 2 months after aspiration, biopsy specimens obtained 1 year later stained positive for iron. Diagnosis of iron pill aspiration was based on these findings, along with the patient's ongoing airway inflammation of the truncus and left lower lobe bronchus and fibrosis. She was treated successfully with balloon bronchoplasty and topical mitomycin C therapy (Lee et al, 2002).
d) CASE REPORT: Severe aspiration pneumonia was reported in a 25-year-old woman following the ingestion of 200 mL of ferric chloride (equivalent to 11.52 grams (230 mg/kg) of elemental iron); the patient died within 4 hours of exposure from a cardiac arrest (Wu et al, 1998).
e) CASE SERIES: Sixteen cases of ferric chloride poisoning between the years of 1990-2001 were analyzed, and aspiration pneumonia was reported in 18.8% of patients (Wu et al, 2003).

D) PNEUMOCONIOSIS

1) WITH POISONING/EXPOSURE

a) Inhaling dust containing iron oxide can lead to pneumoconiosis, but no definitive conclusions as to its role in lung cancer. Based on animal data, iron oxide dust is suspected as a "co-carcinogenic" substance (ILO, 1998). Although it is considered by IARC to be group 3.

1) Iron oxide particles or dust may be caught in the remaining iron oxide accumulates in lymphoid tissue along bronchi, around blood vessels, or at the bifurcation of bronchi(Harbison, 1998a).

E) DECREASED RESPIRATORY FUNCTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 28-year-old pregnant woman, at 32-week gestation, presented with vomiting, lethargy, and respiratory depression within 10 hours of ingesting an unknown amount of an iron supplement. Vital signs included blood pressure of 107/75 mmHg, heart rate of 63 beats/min, and a temperature of 36.4 degrees C. Laboratory results revealed an iron concentration of 470 mcg/dL, potassium 3.3 mEq/L, lactate 1.9 mmol/L, pH 7.4, PCO2 28.7, and HCO3 22 mEq/L. The fetal heart rate was normal. Her condition deteriorated and she became hypotensive (90/50 mmHg) and active labor started. Despite supportive care, including deferoxamine therapy, her mental status did not improve. After the delivery of her infant, 8 hours after presentation, her mental status gradually improved and deferoxamine therapy was discontinued about 24 hours after presentation. An iron concentration from venous umbilical cord blood was 67 mcg/dL (normal about 100 mcg/dL). Laboratory results from the infant revealed a transient acidosis (pH 7.17, PCO2 49, PO2 62), which resolved with airway management (Eggleston & Stork, 2015).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) Lethargy, restlessness and/or confusion have been noted (30 minutes to 2 hours) (Eggleston & Stork, 2015; Carlsson et al, 2008; Chyka & Butler, 1993).
b) CASE REPORT: An 18-year-old woman presented with persistent vomiting, abdominal pain, lethargy, altered mental status, tachycardia (124 beats/min), and severe anion gap metabolic acidosis about 8 hours after ingesting 50 ferrous sulfate tablets (100 mg of elemental iron per 335 mg tablet; 100 mg/kg of elemental iron). Following supportive care, including gastric lavage, whole bowel irrigation, continuous renal replacement therapies, continuous venovenous hemodiafiltration, and deferoxamine therapy, her condition gradually improved. Her serum iron concentration decreased from 2150 to 160 mcg/dL (reference range: 40 to 150 mcg/dL) 24 hours after ingestion (Gumber et al, 2013).

B) SEIZURE

1) WITH POISONING/EXPOSURE

a) Seizures and coma may be seen in Phase III or IV (2 hours to 4 days) (Chyka & Butler, 1993).

3.7.3)

A) ANIMAL STUDIES

1) CNS EFFECTS

a) NMRI mice at 10 to 12 days postnatal were orally treated with 0 mg/kg (no treatment), 3.7 mg/kg (low dose), or 37 mg/kg (high dose) of ferrous iron. A dose-response relationship was seen when testing for spontaneous motor behavior. At 3 months of age, lack of habituation of spontaneous activity was observed for treated animals in the test chambers. Also at 3 months, attenuated performance increments on successive trials were observed in radial arm maze (Fredriksson et al, 1999).

1) Animals from the high dose group also showed more errors in arm choices and longer latencies to acquire all pellets. Analysis of iron content in the brain of animals from the high dose group showed significantly more in the basal ganglia, but not frontal cortex.

Gastrointestinal

3.8.2)

A) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Hemorrhage, ulceration and necrosis of the esophagus, stomach, and bowel are common autopsy findings in fatal iron overdoses.
b) Gastrointestinal hemorrhage may be seen in the first few hours after ingestion.
c) CASE REPORT: After ingestion of enteric-coated iron tablets, 2 adults were noted to have distal isolated small bowel abnormalities. One patient had a 20 cm infarcted segment, and the other patient had a 30 cm stricture (Tenenbein et al, 1990).
d) CASE REPORT: A 47-year-old man who presented to the ED with signs of shock and coma, later developed renal failure, anion gap metabolic acidosis, acute respiratory distress syndrome (ARDS), and liver failure. His medication history showed that he had been using ferrous fumarate. Laboratory results revealed a serum iron concentration of 41 mcmol/L (10 to 30 mcmol/L) on admission. He was treated with desferrioxamine which decreased the serum iron concentration to 23 mcmol/L within 3 days; however, he developed massive gastrointestinal bleeding 4 weeks after presentation and he died despite receiving blood transfusions (Wolters et al, 2014).

B) PYLORIC STENOSIS

1) WITH POISONING/EXPOSURE

a) Obstruction secondary to gastric or pyloric scarring from iron's corrosive effects rarely occurs 2 to 4 weeks after overdose.

C) MUCOSAL ULCER

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An 84-year-old woman with a history of dementia developed a grade II A corrosive injury after ingesting the contents of 1 hand warmer (50% iron powder). The woman presented to the hospital approximately 9 hours after ingestion. Upper endoscopy revealed a large black mass with iron adherent to the mucosa of the esophagus and stomach, friable mucosa with erosions that bled on touch, and whitish membranes with exudates were found in the esophagus and stomach. The mass coated the lining of the stomach, and removal was not possible. Iron concentrations 21 hours after ingestion were 223 mcg/dl. The patient was treated for acute iron intoxication with deferoxamine and proton pump inhibitors. Nine hours after treatment, iron levels decreased to 5 mcg/dl. She was observed for 84 hours and discharged without further sequelae (Tseng et al, 2011).

D) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE

1) WITH POISONING/EXPOSURE

a) Nausea, vomiting, and diarrhea may develop following an overdose (Fil et al, 2015; Eggleston & Stork, 2015; Carlsson et al, 2008; Wu et al, 2003; Gumber et al, 2013).
b) CASE REPORT (PEDIATRIC): An 18-month-old who had ingested 442 mg/kg of elemental iron (5300 mg iron), presented with vomiting dark, but not bloody, material containing lots of dark tablet remnants (Carlsson et al, 2008).
c) CASE SERIES: Sixteen cases of ferric chloride poisoning between the years of 1990-2001 were analyzed. Nausea and vomiting was reported in 68.8% of patients, abdominal pain in 37.5%, and diarrhea in 12.5% of patients (Wu et al, 2003).
d) CASE REPORT: An 18-year-old woman presented with persistent vomiting, abdominal pain, lethargy, altered mental status, tachycardia (124 beats/min), and severe anion gap metabolic acidosis about 8 hours after ingesting 50 ferrous sulfate tablets (100 mg of elemental iron per 335 mg tablet; 100 mg/kg of elemental iron). Following supportive care, including gastric lavage, whole bowel irrigation, continuous renal replacement therapies, continuous venovenous hemodiafiltration, and deferoxamine therapy, her condition gradually improved. Her serum iron concentration decreased from 2150 to 160 mcg/dL (reference range: 40 to 150 mcg/dL) 24 hours after ingestion (Gumber et al, 2013).
e) CASE REPORT: A 32-year-old woman developed a "warm sensation" in her mouth and epigastrium after ingesting a piece of a hand warmer containing 5 to 8 grams of elemental iron. Laboratory results revealed a serum iron concentration of 235 mcg/dL obtained 6 hours postingestion (Weiland & Sherrow, 2015).

Hepatic

3.9.2)

A) INJURY OF LIVER

1) WITH POISONING/EXPOSURE

a) BACKGROUND: Hepatotoxicity leading to death can occur following acute iron poisoning. Based on a review of the literature, patients developed hepatotoxicity within 24 to 48 hours and effects appear to be dose related. The primary site of hepatic injury is the periportal areas of the hepatic lobule (the principal site for hepatic regeneration), which may explain the increase in mortality and poorer prognosis. Rapid onset and periportal injury were also consistently reported in animal studies due to iron poisoning (Tenenbein, 2001).
b) MECHANISM: Iron-induced hepatotoxicity is a presumed result of free radical generation and lipid peroxidation. Iron catalyzes hydroxyl radical formation (the most potent-free radical), which initiates lipid peroxidation. Based on limited data, antioxidants may have a hepatoprotective role in iron poisoning. Further research is suggested to establish efficacy (Tenenbein, 2001).
c) INCIDENCE: Periportal hepatic necrosis is described in fatal cases, although it occurs rarely (McGuigan, 1996). Significant elevations of AST, ALT, LDH, and bilirubin occur 1 to 4 days postingestion in severe cases (Gleason, 1979; Comes et al, 1993).
d) DOSE-DEPENDENT RELATIONSHIP: Robertson & Tenenbein (2005) looked at 73 cases of iron poisoning to determine if hepatotoxicity due to iron poisoning is a dose-related effect. Sixty patients had no signs of hepatotoxicity, 4 patients developed mild hepatotoxicity, and 9 patients developed severe hepatotoxicity (transaminase greater than 1000 Units/L). The serum iron levels of only 3 patients with severe hepatotoxicity were obtained early and prior to deferoxamine therapy. The values ranged from 1821 to 20,900 mcg/dL. The authors concluded that clinically significant hepatotoxicity is not likely to occur with serum iron levels less than 700 mcg/dL (Robertson & Tenenbein, 2005).
e) CASE REPORT: An 18-year-old woman intentionally ingested 100 ferrous sulfate tablets (120 mg/kg elemental iron) and presented to the hospital approximately 5 hours later. A serum iron level at 6 hours post-ingestion was 340 mcg/dL, and the patient underwent gastric lavage in addition to initiating deferoxamine therapy. On hospital day 2, ALT rose to greater than 4000 Units/L, and prothrombin and bilirubin began to increase. Treatment with deferoxamine continued and N-acetylcysteine was added. The patient made a full recovery over the next few days.

1) The author's note that this patient's serum iron peak of 340 mcg/dL is much lower than levels previously reported in cases of hepatotoxicity, and suggest some component of an idiosyncratic reaction to explain the hepatotoxicity in this case (Daram & Hayashi, 2005).

f) CASE REPORT: An 18-month-old boy (weight 11 kg) presented with diarrhea and vomiting after ingesting about 1625 mg (147 mg/kg) of ferrous sulfate. He later became drowsy, requiring intubation and ventilation. X-ray of the abdomen revealed 13 tablet fragments. Despite standard therapy (gastric lavage, whole bowel irrigation, and intravenous deferoxamine 15 mg/kg/hr, total at least 360 mg/kg in 24 hours), his serum iron concentration increased to 700 mcmol/L (3906 mcg/dL) 6 hours after ingestion. He developed elevated ALT (359 Units/L) and coagulopathy with kaolin partial thromboplastin time at 74.5 s and prothrombin time at 16.5 s, requiring vitamin K, fresh frozen plasma, and cryoprecipitate. Approximately 14 hours postingestion, he underwent continuous veno-venous hemofiltration (CVVH) for 17 hours and his serum iron concentration quickly decreased to 24.5 mcmol/L (137 mcg/dL). Despite signs of organ damage, he gradually recovered and was discharged on day 5 (Milne & Petros, 2010).

B) HEPATIC FAILURE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 3-year-old girl ingested an unknown number of 325 mg ferrous sulfate tablets. Initial labs taken at 6 hours revealed a serum iron level of 21,680 mcg/dL. Therapy included endotracheal intubation, copious IV fluids, whole bowel irrigation (up to 500 mL/hour) and deferoxamine (up to 30 mg/kg/hour). The patient developed fulminant hepatic failure, coagulopathy (PT peak 54 sec), GI bleeding, and hypoglycemia. Coagulopathy could not be corrected. On hospital day 3, AST and ALT peaked at 11,060 and 7,140 International Units/L. On hospital day 6, liver transplant was successfully performed with patient surviving (Comes et al, 1993).
b) CASE REPORT: A 17-year-old girl presented with 4 episodes of non-bloody vomiting, epigastric abdominal pain, and mild somnolence 2 hours after ingesting 10 ferrous sulfate 325 mg tablets. Serum iron concentrations were 1000 mcg/dL at 2 hours and 670 mcg/dL at 4 hours. Laboratory results revealed a WBC of 14.9 x 10(3)/L, glucose 233 mmol/L, anion gap of 22, pH 7.25, bicarbonate of 14 mEq/L, and INR of 1.87. Despite supportive treatment, including deferoxamine therapy for 24 hours, her INR increased to 6.59 and liver enzymes, AST and ALT, increased from normal levels to 2436 Units/L and 3309 Units/L, respectively. Her INR increased further to greater than 13 after she was transferred to a liver transplant center. She received a liver transplant 5 days postingestion. Liver pathology result was consistent with massive hepatic necrosis compatible with toxin-induced liver injury (ie, diffuse parenchymal collapse, severe cholestasis and formation of ductular hepatocytes) (Fil et al, 2015).
c) CASE REPORT: A 17-year-old girl intentionally ingested 69 iron tablets (approximately 30 mg/kg elemental iron) along with 4 grams ibuprofen, 40 tablets of a cold preparation (each containing 10 mg noscapine hydrochloride, 30 mg caffeine, 150 mg phenazonesalicylate, 200 mg salicylamide, and 200 mg ascorbic acid), and a bottle of wine. Initial serum iron level approximately 3 hours after ingestion was 1076 mcmol/L, and deferoxamine (35 mg/hour) was given for 14 hours. Despite therapy the patient developed grade III encephalopathy several days after exposure and required emergent liver transplantation. Based on the increased level of iron absorption, the authors suggested that the patient may have had developed hemochromatosis, since the serum iron level was higher and the degree of liver injury much more severe than would have been expected based on the amount ingested. At 6 month follow-up, liver function was normal and the most common genetic marker for hemochromatosis was negative (Taalikka et al, 1999).
d) CASE REPORT: A 47-year-old man who presented to the ED with signs of shock and coma, later developed renal failure, anion gap metabolic acidosis, acute respiratory distress syndrome (ARDS), and liver failure. His medication history showed that he had been using ferrous fumarate. Laboratory results revealed a serum iron concentration of 41 mcmol/L (10 to 30 mcmol/L) on admission. He was treated with desferrioxamine which decreased the serum iron concentration to 23 mcmol/L within 3 days; however, he developed massive gastrointestinal bleeding 4 weeks after presentation and he died despite receiving blood transfusions (Wolters et al, 2014).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute renal failure may develop after severe overdoses secondary to shock or hepatic necrosis.
b) CASE REPORT: A 47-year-old man who presented to the ED with signs of shock and coma, later developed renal failure, anion gap metabolic acidosis, acute respiratory distress syndrome (ARDS), and liver failure. His medication history showed that he had been using ferrous fumarate. Laboratory results revealed a serum iron concentration of 41 mcmol/L (10 to 30 mcmol/L) on admission. He was treated with desferrioxamine which decreased the serum iron concentration to 23 mcmol/L within 3 days; however, he developed massive gastrointestinal bleeding 4 weeks after presentation and he died despite receiving blood transfusions (Wolters et al, 2014).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Anion gap metabolic acidosis is a common early finding in significant ingestions (Carlsson et al, 2008; Schonfeld & Haftel, 1989; Wu et al, 1998). Severe metabolic acidosis may persist for days in severe overdoses.
b) CASE SERIES: Sixteen cases of ferric chloride poisoning between the years of 1990-2001 were analyzed, and metabolic acidosis was reported in 25% of patients (Wu et al, 2003).
c) CASE REPORT

1) INTENTIONAL ABUSE: A 7-week-old male was admitted with reported constipation, metabolic acidosis, (arterial blood gas on admission: pH 7.09; PC02 32 and base deficit -19.6) and significant dehydration. Clinical evidence suggested an initial diagnosis of bowel obstruction, but persistent symptoms of acidosis and a lack of maternal concern led to the mother admitting to "crushing a few iron tablets" and feeding them to the infant. The iron level from the first 36 hours of admission were reported as 308 mcg/dL (normal 50 to 170 mcg/dL) (Black & Zenel, 2003).
2) A 28-year-old pregnant woman, at 32-week gestation, presented with vomiting, lethargy, and respiratory depression within 10 hours of ingesting an unknown amount of an iron supplement. Vital signs included blood pressure of 107/75 mmHg, heart rate of 63 beats/min, and a temperature of 36.4 degrees C. Laboratory results revealed an iron concentration of 470 mcg/dL, potassium 3.3 mEq/L, lactate 1.9 mmol/L, pH 7.4, PCO2 28.7, and HCO3 22 mEq/L. The fetal heart rate was normal. Her condition deteriorated and she became hypotensive (90/50 mmHg) and active labor started. Despite supportive care, including deferoxamine therapy, her mental status did not improve. After the delivery of her infant, 8 hours after presentation, her mental status gradually improved and deferoxamine therapy was discontinued about 24 hours after presentation. An iron concentration from venous umbilical cord blood was 67 mcg/dL (normal about 100 mcg/dL). Laboratory results from the infant revealed a transient acidosis (pH 7.17, PCO2 49, PO2 62), which resolved with airway management (Eggleston & Stork, 2015).
3) A 47-year-old man who presented to the ED with signs of shock and coma, later developed renal failure, anion gap metabolic acidosis, acute respiratory distress syndrome (ARDS), and liver failure. His medication history showed that he had been using ferrous fumarate. Laboratory results revealed a serum iron concentration of 41 mcmol/L (10 to 30 mcmol/L) on admission. He was treated with desferrioxamine which decreased the serum iron concentration to 23 mcmol/L within 3 days; however, he developed massive gastrointestinal bleeding 4 weeks after presentation and he died despite receiving blood transfusions (Wolters et al, 2014).
4) An 18-year-old woman presented with persistent vomiting, abdominal pain, lethargy, altered mental status, tachycardia (124 beats/min), and severe anion gap metabolic acidosis (pH 7.16, PaO2 122 mmHg, PCO2 20 mmHg, bicarbonate 6.9 mmol/L, base excess -21.5 mmol/L) about 8 hours after ingesting 50 ferrous sulfate tablets (100 mg of elemental iron per 335 mg tablet; 100 mg/kg of elemental iron). Following supportive care, including gastric lavage, whole bowel irrigation, continuous renal replacement therapies, continuous venovenous hemodiafiltration, and deferoxamine therapy, her condition gradually improved. Her serum iron concentration decreased from 2150 to 160 mcg/dL (reference range: 40 to 150 mcg/dL) 24 hours after ingestion (Gumber et al, 2013).

3.11.3)

A) ANIMAL STUDIES

1) ACIDOSIS

a) In a dog model of iron poisoning, metabolic acidosis was observed immediately and persisted despite bicarbonate administration and supportive care (Vernon et al, 1989).

Hematologic

3.13.2)

A) BLOOD COAGULATION PATHWAY FINDING

1) WITH POISONING/EXPOSURE

a) Early coagulopathy (4 to 8 hours postingestion) has been reported rarely and may be due to interference with enzymes of the coagulation cascade by free iron (Tenenbein & Israels, 1988). It is related to plasma concentrations of ferric iron.
b) Late coagulopathy (24 hours or more postingestion) is associated with severe hepatotoxicity and decreased levels of factors V, VII, IX, X, and fibrinogen (Tenenbein & Israels, 1988).
c) CASE REPORT: An 18-month-old boy (weight 11 kg) presented with diarrhea and vomiting after ingesting about 1625 mg (147 mg/kg) of ferrous sulfate. He later became drowsy, requiring intubation and ventilation. X-ray of the abdomen revealed 13 tablet fragments. Despite standard therapy (gastric lavage, whole bowel irrigation, and intravenous deferoxamine 15 mg/kg/hr, total at least 360 mg/kg in 24 hours), his serum iron concentration increased to 700 mcmol/L (3906 mcg/dL) 6 hours after ingestion. He developed elevated ALT (359 Units/L) and coagulopathy with kaolin partial thromboplastin time at 74.5 s and prothrombin time at 16.5 s, requiring vitamin K, fresh frozen plasma, and cryoprecipitate. Approximately 14 hours postingestion, he underwent continuous veno-venous hemofiltration (CVVH) for 17 hours and his serum iron concentration quickly decreased to 24.5 mcmol/L (137 mcg/dL). Despite signs of organ damage, he gradually recovered and was discharged on day 5 (Milne & Petros, 2010).

B) HEMOCHROMATOSIS

1) WITH POISONING/EXPOSURE

a) Hemochromatosis may rarely occur after chronic ingestion of excessive iron (Green et al, 1989). Patients receiving parenteral iron therapy may be at more risk to develop iron overload because the intestinal regulatory mechanisms are bypassed (Burns & Pomposelli, 1999).

C) LEUKOCYTOSIS

1) WITH POISONING/EXPOSURE

a) Leukocyte counts greater than 15,000/mm(3) have been reported following iron poisoning, but is nonspecific (Lacouture et al, 1981; Mann et al, 1989).
b) In one series, a high WBC and plasma glucose correlated with a serum iron level greater than 300 mcg/dL (Lacouture et al, 1981); in other series this correlation could not be found Chyka & Butler, 1992; Palatnick & Tenenbein, 1992(Knasel & Collins-Barrow, 1986).

Dermatologic

3.14.2)

A) CHEMICAL BURN

1) WITH POISONING/EXPOSURE

a) THERMAL BURN: CASE REPORT: A ferrous sulfate slurry heated to 65 degrees Celsius produced a 75% BSA burn (Chang et al, 1988). This patient's course followed that of an oral ingestion. The cytotoxic properties of iron may have contributed to the full thickness burn in this patient.

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) Serum glucose concentration greater than 150 mg/dL has been reported (Lacouture et al, 1981; Mann et al, 1989).

B) HYPOGLYCEMIA

1) WITH POISONING/EXPOSURE

a) Hypoglycemia secondary to hepatic failure may be seen late (2 to 4 days) in severe overdoses.

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) Reports of anaphylactoid reactions have occurred with therapeutic administration of parenteral iron (Burns & Pomposelli, 1999). In one study, doses of 500 mg or more were associated with severe reactions.

Reproductive

3.20.1)

A) Ferric citrate, iron sucrose, and the sodium ferric gluconate complex have been classified by the manufacturers as FDA pregnancy category B. Various iron salts are used therapeutically to correct iron deficiency in pregnancy. Iron-deficiency anemia has been associated with an increased risk of preterm delivery and low birth weight. There are no adequate or well-controlled studies of ferric pyrophosphate citrate use during pregnancy. Because ferric pyrophosphate citrate may cause fetal harm, advise female patients of reproductive potential to use effective contraception while using the drug and for at least 2 weeks after ending treatment. It is not known whether sodium ferric gluconate complex is excreted into human breast milk.
B) Case reports of pregnant women who have received early aggressive treatment (decontamination and/or deferoxamine) for iron overdose have described good fetal outcomes.

3.20.2)

A) ANIMAL STUDIES

1) FERRIC CITRATE

a) Skeletal and encephalic malformations were reported in neonatal animals following administration of intraperitoneal ferric gluconate in gravid dams on gestation days 7 through 9 (Prod Info AURYXIA(TM) oral tablets, 2016).

2) FERRIC PYROPHOSPHATE CITRATE

a) In animal reproduction studies, no teratogenic effects were noted after the administration of ferric pyrophosphate citrate during organogenesis at doses 96 and 128 times the maximum recommended human dose (Prod Info TRIFERIC(R) not applicable solution, 2016).

1) RATS, RABBITS: During a fertility and early embryonic development study in female rats, the administration of IV ferric pyrophosphate citrate 40 mg/kg 3 times weekly was deemed maternally toxic but not toxic to the embryo. In an embryofetal developmental toxicity study, the administration of IV ferric pyrophosphate citrate during organogenesis to pregnant rats and rabbits resulted in no maternal or developmental toxicities at doses up to 30 mg/kg/day and 20 mg/kg/day, respectively. Post-implantation loss, abnormal placentae, decreased fetal body weights, and fetal head and vertebral malformations were reported at doses of 90 m/gk/day in rats. Vertebral malformations were reported at doses of 40 mg/kg/day in rabbits. Finally, in a pre- and postnatal developmental study in pregnant rats, the administration of IV ferric pyrophosphate citrate up to 90 mg/kg/day resulted in maternal toxicity, reduced numbers of live offspring, and lower offspring body weights. There were no reports of adverse effects on behavior, sexual maturation, or reproductive parameters at any dose, nor were there any effects on offspring survival at doses up to 30 mg/kg/day (Prod Info TRIFERIC(R) not applicable solution, 2016).

3) IRON DEFICIENCY

a) The nutritional requirement for iron is higher during pregnancy, because the fetus needs iron for synthesis of iron-containing proteins. Iron deficiency has caused resorptions in pregnant animals. Iron deficiency during the first 2 trimesters of pregnancy was associated with 3 times the risk of low birth weight and more than twice the risk of prematurity (Scholl & Hediger, 1994).
b) RATS: Pregnant rats given an iron-deficient diet had pups with lower hematocrit, hemoglobin, and hepatic iron levels than controls, and higher levels of hepatic zinc and copper. These effects were reversible (Arce & Keen, 1993).
c) SHEEP: No elevation of fetal serum iron concentration was observed up to 4 hours after IV administration of 2 mg/kg of iron over 60 minutes to pregnant sheep (Curry et al, 1990). However, the pharmacokinetics of iron across the placenta of sheep may not be the same as in humans.

4) IRON SUCROSE

a) During animal reproduction studies, administration of IV iron sucrose during organogenesis (at doses half of or equal to the maximum recommended human dose) showed no evidence of fetal harm (Prod Info Venofer(R) intravenous injection, 2015).

5) SODIUM FERRIC GLUCONATE COMPLEX

a) MICE, RATS: In animal studies, there was no teratogenicity in mice and rats administered sodium ferric gluconate complex at doses up to 100 mg/kg/day and 20 mg/kg/day (approximately 4 and 1.5 times the recommended human dose of 125 mg/day, respectively, based on body surface area), respectively (Prod Info Ferrlecit(R) intravenous injection, 2014).

3.20.3)

A) PREGNANCY CATEGORY

1) FERRIC CITRATE

a) The manufacturer has classified ferric citrate as FDA pregnancy category B (Prod Info AURYXIA(TM) oral tablets, 2016).
b) No adequate or well-controlled studies of ferric citrate in pregnant women have been published. The effect of ferric citrate alone or on the absorption of vitamins and other nutrients has not been studied during pregnancy. Although requirements for vitamins and other nutrients are higher during pregnancy, an overdose of iron in a pregnant woman may increase the risk of spontaneous abortion and fetal malformation. Due to the lack of human safety information, administer ferric citrate to pregnant women only if the potential benefit outweighs the potential risk to the fetus (Prod Info AURYXIA(TM) oral tablets, 2016).

2) FERRIC PYROPHOSPHATE CITRATE

a) There are no adequate or well-controlled studies of ferric pyrophosphate citrate use during pregnancy. Because ferric pyrophosphate citrate may cause fetal harm, advise female patients of reproductive potential to use effective contraception while using the drug and for at least 2 weeks after ending treatment (Prod Info TRIFERIC(R) not applicable solution, 2016).

3) IRON SUCROSE

a) The manufacturer has classified iron sucrose as FDA pregnancy category B (Prod Info Venofer(R) intravenous injection, 2015).
b) There are no adequate and well-controlled studies in pregnant women. Administer iron sucrose during pregnancy, only if clearly needed (Prod Info Venofer(R) intravenous injection, 2015).

4) SODIUM FERRIC GLUCONATE COMPLEX

a) The manufacturer has classified sodium ferric gluconate complex as FDA pregnancy category B (Prod Info Ferrlecit(R) intravenous injection, 2014).
b) Although there are no adequate and well-controlled studies of sodium ferric gluconate complex in pregnant women and teratogenicity was not evident in animal studies, the manufacturer recommends the use of sodium ferric gluconate complex in pregnant women only if clearly needed. Sodium ferric gluconate complex contains benzyl alcohol and although there is no evidence of fetal exposure to benzyl alcohol through maternal use, administration via IV can cause serious adverse events, including death, in exposed neonates and infants (Prod Info Ferrlecit intravenous injection, 2011).

B) ACUTE TOXICITY

1) OVERDOSE: Case reports of pregnant women who have overdosed on iron and received early aggressive treatment, including decontamination and deferoxamine chelation, have described good fetal outcomes (Lacoste et al, 1992; (Blanc et al, 1984; Rayburn et al, 1983; Tenenbein, 1989a).

a) In contrast, both maternal and fetal fatalities have been described in cases where deferoxamine treatment was delayed or withheld (Olenmark et al, 1987; Manoguerra, 1976; Strom et al, 1976).
b) CASE REPORT: A 28-year-old pregnant woman, at 32-week gestation, presented with vomiting, lethargy, and respiratory depression within 10 hours of ingesting an unknown amount of an iron supplement. Vital signs included blood pressure of 107/75 mmHg, heart rate of 63 beats/min, and a temperature of 36.4 degrees C. Laboratory results revealed an iron concentration of 470 mcg/dL, potassium 3.3 mEq/L, lactate 1.9 mmol/L, pH 7.4, PCO2 28.7, and HCO3 22 mEq/L. The fetal heart rate was normal. Her condition deteriorated and she became hypotensive (90/50 mmHg) and active labor started. Despite supportive care, including deferoxamine therapy, her mental status did not improve. After the delivery of her infant, 8 hours after presentation, her mental status gradually improved and deferoxamine therapy was discontinued about 24 hours after presentation. An iron concentration from venous umbilical cord blood was 67 mcg/dL (normal about 100 mcg/dL). Laboratory results from the infant revealed a transient acidosis (pH 7.17, PCO2 49, PO2 62), which resolved with airway management (Eggleston & Stork, 2015).
c) CASE REPORT: A 30-year-old woman, who ultimately expired 2 weeks after an iron overdose, delivered a healthy infant by caesarean section 31 hours after the overdose. Deferoxamine therapy was not started until 26 hours after ingestion (Olenmark et al, 1987).
d) CASE REPORT: A 24-year-old woman at 34 weeks gestation overdosed on an unknown quantity of ferrous sulfate. After gastrointestinal decontamination, deferoxamine therapy was initiated and 10 hours later a spontaneous vaginal delivery occurred. Both the mother and the infant did well in this case (Rayburn et al, 1983).
e) CASE REPORT: A 15-year-old prima gravida patient overdosed on iron at 15 weeks gestational age. Chelation therapy was administered successfully in this case. Subsequently, a normal spontaneous vaginal delivery occurred producing a female infant without evidence of congenital malformations (Blanc et al, 1984).
f) Spontaneous abortion has occurred during resuscitation of the mother (Manoguerra, 1976).

2) CASE SERIES: In a series of 5 pregnant women who overdosed on iron, 3 were treated with deferoxamine. Serum iron levels ranged from 457 to 594 mcg/dL and all exceeded the TIBC. All women fully recovered. Four delivered normal infants at term and one obtained a therapeutic abortion (Tenenbein, 1989a).
3) CASE SERIES: In one case study of 49 pregnant iron overdose patients, 43 of the pregnancies (88%) resulted in live babies. Of the 25 patients treated with deferoxamine, 20 (80%) delivered healthy, full-term babies (McElhatton et al, 1991).

a) Twenty-eight (57%) of all patients had taken over 20 mg/kg of iron. Six of these had serum levels of greater than or equal to 90 mcmol/L, and all six delivered healthy, full-term babies after gastric decontamination and deferoxamine therapy (McElhatton et al, 1991).

4) CASE SERIES: A review of 61 cases of obstetric iron overdose found that patients with peak iron levels greater than 400 mcg/dL were more frequently symptomatic (p=0.05), but having a peak iron level greater than 400 mcg/dL was NOT associated with increased risk of spontaneous abortion, preterm delivery, congenital anomalies, or maternal death (Tran et al, 2000).

a) An association was found between those patients who progressed to stage 3 iron toxicity (organ failure) and spontaneous abortion (1/3 vs 1/56; p=0.02), preterm delivery (2/3 vs 6/56; p=0.02), and maternal death (3/3 vs 0/56; p=0.00003) compared to women with less advanced toxicity (Tran et al, 2000).

C) CHRONIC TOXICITY

1) CASE REPORT: An 18-year-old transfusion-dependent pregnant Thalassemic patient was treated with subcutaneous deferoxamine until 16 weeks of gestation. The infant was born at 33 weeks by emergency caesarean section due to a third trimester hemorrhage and spontaneous rupture of membranes. The neonate's course was complicated by hypoglycemia and hyperbilirubinemia (Thomas & Skalicka, 1980).
2) INCREASED ABSORPTION: Absorption efficiency of non-heme dietary iron increases 9 fold between weeks 12 and 36 of gestation, enough to meet the increased demand for iron through dietary means alone. Iron supplementation during normal pregnancy is of questionable value (Barrett et al, 1994).
3) PREGNANCY-INDUCED HYPERTENSION: There was a linear relationship between serum iron levels and diastolic blood pressure at termination of pregnancy (r=0.75) in a prospective study with a group of 54 affected women. Serum iron levels of 110 mcg/dL or greater were associated with pregnancy-induced hypertension (Das et al, 1994).

D) BIRTH PREMATURE

1) There is a 3-fold increase in premature births in women with iron deficiency anemia that is apparent early in pregnancy (Turkay et al, 1995). The benefits of routine nutritional iron supplementation during pregnancy are controversial (Roodenburg, 1995). It is unclear whether or not iron supplementation during pregnancy improves prenatal or postnatal development of the child (Beaufrere et al, 1995). In one study with 27 pregnant women, there was no correlation between maternal ferritin or hemoglobin levels and birth weight, gestational age at birth, or hemoglobin in the newborn (Turkay et al, 1995). In another study, elevated maternal ferritin levels were related to spontaneous preterm deliveries (Tamura et al, 1996).
2) Various iron salts are used therapeutically to correct iron deficiency in pregnancy. Iron deficiency anemia was associated with an increased risk for preterm delivery and low birth weight in a group of inner-city women (Allen, 1993).

E) HYPERTENSION

1) Absorption of non-heme iron from food increased during pregnancy, from 7% at 12 weeks gestation to 66% at 36 weeks, enough to meet the increased need for iron when there were adequate amounts of iron in the diet. Nutritional iron supplementation in normal pregnancies is of questionable value (Barrett et al, 1994). Serum iron levels greater than or equal to 110 mcg/dL were associated with pregnancy-induced hypertension in a group of 54 women (Das et al, 1994).

F) PLACENTAL BARRIER

1) The hemoglobin, hematocrit, and erythrocyte counts of the fetus parallel those of the mother. In one Spanish study, when maternal ferritin levels fell below 12 mcg/L, ferritin levels in cord blood were lower (80.4 mcg/L versus 123 mcg/L) (Gaspar et al, 1993).

3.20.4)

A) LACK OF INFORMATION

1) BREAST MILK

a) FERRIC CITRATE

1) Iron was transferred into the milk of lactating animals via divalent metal transporter-1 and ferroportin-1. Therefore, infants may be exposed to ferric citrate during breastfeeding (Prod Info AURYXIA(TM) oral tablets, 2016).

b) FERRIC PYROPHOSPHATE CITRATE

1) No reports describing the use of ferric pyrophosphate citrate during human lactation are available, and the effects on the nursing infant are unknown. It is unknown whether ferric pyrophosphate citrate is excreted into human milk. Because many drugs are excreted in human milk and risk to the nursing infant cannot be excluded, a decision should be made to discontinue nursing or discontinue ferric pyrophosphate citrate, taking into account the importance of the drug to the mother (Prod Info TRIFERIC(R) not applicable solution, 2016).

c) IRON SUCROSE

1) Exercise caution when administering iron sucrose to a lactating woman (Prod Info Venofer(R) intravenous injection, 2015).
2) With supplementation, iron excreted in the breast milk is approximately 0.25 mg/day during normal lactation(Harju, 1989a).
3) Fifteen mothers with functional iron deficiency and mild anemia were administered either a single dose of 100 mg intravenous iron sucrose (n=10) or nothing (n=5), and it was found that the mean concentrations of iron in the breast milk for both groups at baseline through day 4 were not significantly different between groups. The authors conclude that the administration of 100 mg intravenous iron sucrose did not increase iron content of the colostrum, and iron levels in the breast milk fell within the range of untreated healthy mothers. Additionally, these results agree with those from studies of postpartum mothers with or without oral iron supplementation. These findings support the assumption that breastfed infants are protected from iron overload via the regulation of milk iron concentration by active mammary gland mechanisms (Breymann et al, 2007)

d) SODIUM FERRIC GLUCONATE COMPLEX

1) It is not known whether sodium ferric gluconate complex is excreted in human breast milk. Benzyl alcohol, a component of sodium ferric gluconate complex, is known to be excreted in human breast milk and may be absorbed by a nursing infant. Because many drugs are excreted in human milk, there is the potential for adverse reactions in nursing infants. Due to the lack of human safety information, the manufacturer recommends administering sodium ferric gluconate complex to nursing women with caution (Prod Info Ferrlecit(R) intravenous injection, 2014). If breastfeeding cannot be avoided, it appears that the breastfeeding infant may be protected from ingesting unsafe levels of iron via mechanisms in the mother's mammary tissue (Breymann et al, 2007).

B) ANIMAL STUDIES

1) FERRIC CITRATE

a) Iron was transferred into the milk of lactating animals via divalent metal transporter-1 and ferroportin-1. Therefore, infants may be exposed to ferric citrate during breastfeeding (Prod Info AURYXIA(TM) oral tablets, 2016).

3.20.5)

A) ANIMAL STUDIES

1) FERRIC CITRATE

a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent; however, skeletal and encephalic malformations were reported in neonatal animals following administration of intraperitoneal ferric gluconate in gravid dams on gestation days 7 through 9 (Prod Info AURYXIA(TM) oral tablets, 2016).

2) FERRIC PYROPHOSPHATE CITRATE

a) No adverse effects on fertility or reproduction were reported following administration of IV ferric pyrophosphate citrate 40 mg/kg 3 times weekly in male and female rats (Prod Info TRIFERIC(R) not applicable solution, 2016).

3) IRON SUCROSE

a) There were no reports of adverse effects on fertility or reproduction in male and female animals administered IV iron sucrose at doses 1.2 times the maximum recommended human dose (Prod Info Venofer(R) intravenous injection, 2015).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS7439-89-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

3.21.2)

A) At the time of this review, no human data were available to assess the potential carcinogenic activity of supplemental iron sucrose. Cases have linked gastric carcinoma with increased plasma ferritin levels and pulmonary, renal, and other cancers with exposure to iron workers in the metal industry.

3.21.3)

A) GASTRIC CARCINOMA

1) COLON CANCER: A dose-related increased risk for adenoma in the colon and serum ferritin levels has been seen retrospectively in a group of 264 men and 98 women who were part of a larger epidemiological study of colon cancer. The odds ratio was 5.1 for ferritin levels in the range of 130 to 256 nanograms/mL (Nelson et al, 1994).
2) Increased risk of mortality from stomach cancer was found in one study, which confirmed an earlier study with suggestive results. The increased risk for lung and stomach cancer was seen in smokers, but not in nonsmokers (Pham et al, 1991; Pham et al, 1983).
3) In the National Health and Nutrition Examination Survey I and the National Health Evaluation Follow-Up Study, elevated serum iron was associated with increased risk for colon cancer in men, and for both colon and rectal cancer in women, during the 15-year period of 1971 to 1986 (Wurzelmann et al, 1996).

a) There was also a weak association with development of colorectal polyps, a precancerous condition, in men and women 50 to 75 years of age (Bird et al, 1996).

4) Proportional relative mortality from stomach, lung, and colorectal cancer were elevated in Chinese iron and steel workers, relative to the general male population, for the period 1980 to 1989. Jobs with direct exposure to iron and coal dust were at highest risk for stomach cancer (Xu et al, 1996).

B) PULMONARY CARCINOMA

1) Several epidemiologic studies have shown a relationship between iron mining and increased mortality from lung cancer (Boyd et al, 1970; Cavelier et al, 1980; Damber & Larsson, 1985; Edling, 1982; Faulds & Stewart, 1956; Gurevich, 1967; Jorgensen, 1973; Lawler et al, 1985) Radfort & St Claire Renard, 1984). In most of these studies, the excess lung cancer risk has been thought to be due to exposure to radon daughters, a source of ionizing radiation. The excess risk of death from lung cancer in iron miners has generally been in the range of 2- to 12-fold.
2) Risk of lung cancer was elevated in workers employed for at least 15 years in smelting and rolling, in a nested case-control study on Chinese iron and steel workers. Risk of stomach cancer was elevated with ore sintering and transportation. The overall increased risk for lung and stomach cancers in these steel workers was 40% after adjusting for known confounders, and was related to total dust exposures (Xu et al, 1996).

a) In some cases, excess cancers can be explained by exposure to other substances, such as polynuclear aromatic hydrocarbons (PAHs) in iron foundry workers. There is a possibility that iron oxide may act as a co-carcinogen by facilitating the uptake of carcinogenic substances, such as those found in cigarette smoke.

C) RENAL CARCINOMA

1) Significantly increased deaths from kidney cancer were seen in workers in the iron and steel industry (Mandel et al, 1995). Mortality from all cancers other than lung, stomach, and rectal was increased in a group of Swedish iron miners. The mortality was not associated with radon exposure, but was at sites consistent with radon-induced cancers (Darby et al, 1995).

D) CARCINOMA

1) In an epidemiological study of 1747 cases of childhood cancer in Denmark, risk was significantly associated with the fathers' occupation, especially in the manufacture of iron and metal structures (Olsen et al, 1991). Other studies have found associations between employment of fathers in the iron and metal industries and childhood cancers (Fabia & Thuy, 1974; Kantor et al, 1979; Kwa & Fine, 1980; Hemminki et al, 1981; Lowengart et al, 1987; Bunin et al, 1989; Wilkins & Sinks, 1990).
2) The carcinogenic activity of iron is due to its ability to promote formation of hydroxyl radicals, suppression of host defense, and promotion of cancer cell division. Primary cancers develop at the sites of excess iron deposits in both animals and humans (Weinberg, 1996). Slight increases in body iron stores have been linked with cancer, but the casual relationship has not been proven (Lynch & Baynes, 1996).

3.21.4)

A) HEPATIC CARCINOMA

1) Iron and its inorganic salts have generally not caused cancer in experimental animals, except when implanted. Increased risk for hepatocellular carcinoma occurs with development of liver cirrhosis from iron overload. Dietary iron did not act as either a promotor or initiator in one experimental animal model (Stal, 1995). Dietary iron enhanced the induction of lung tumors by 4-nitroquinoline-1-oxide in mice (Yano et al, 1994) and promoted diethylnitrosamine-initiated rat liver foci (Carthew et al, 1997).

B) LACK OF EFFECT

1) FERRIC CITRATE: There was no evidence of carcinogenicity in mice and rats when ferric citrate was given IM or subQ (Prod Info Auryxia(TM) oral tablets, 2014).

Genotoxicity

A)

B)

C)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Serial serum iron levels are indicated.
C) Obtain a complete metabolic panel and complete blood count.
D) Baseline arterial or venous blood gas in patients with severe toxicity.
E) Obtain an abdominal radiograph to evaluate for retained tablets.

4.1.2)

A) HEMATOLOGIC

1) Determine CBC (include hematocrit and hemoglobin).

B) BLOOD/SERUM CHEMISTRY

1) Determine electrolytes, serum bicarbonate, blood glucose and serum iron concentration.
2) Peak serum iron concentrations generally occur 4 to 6 hours after overdose (Tenenbein, 1998). Serum iron levels usually fall to normal within 12 to 48 hours with deferoxamine treatment (Westlin, 1966).
3) Monitor liver and renal function tests in patients with severe overdose.

C) COAGULATION STUDIES

1) Monitor INR or PT and PTT in patients with severe poisoning.

Radiographic Studies

A)

1) Obtain abdominal x-ray to evaluate for tablets in the gut and need for decontamination. As dissolution occurs, a diffuse density rather than discrete tablets may be seen.
2) Completely dissolved iron tablets/capsules may not be radiopaque (Jaeger et al, 1981; Ng et al, 1979). A positive abdominal radiograph is more likely to be associated with significant symptoms than a negative x-ray (James, 1970).

Methods

A)

1) TIBC/SUMMARY - rises factitiously in the presence of high concentrations of iron (Tenenbein & Yatscoff, 1989; Burkhart et al, 1991) or iron dextran (Hanchelroad & Rice, 1992) and the TIBC often exceeds the serum iron level in symptomatic patients (Chyka & Brady, 1989; Burkhart et al, 1991). For these reasons, the TIBC fails as a marker of iron toxicity in acute overdoses (Siff et al, 1999).

a) Other clinical considerations (signs and symptoms, metabolic acidosis, presence of iron on radiograph) should be used to determine need for chelation.
b) Siff et al (1999) noted that in a review of the literature, TIBC levels may not be a useful predictor of end-organ toxicity, nor an appropriate guide to deferoxamine therapy. The following reasons may limit its usefulness in the setting of overdose:

1) In acute overdose, all methods of TIBC determination may be inaccurate; the presence of deferoxamine has been shown to cause an inaccurate TIBC; variability in TIBC readings; and lastly toxicity has been observed even when the TIBC level were greater than the serum iron concentration.

a) In a clinical chemistry quality assessment program, interlaboratory variability of TIBC determination reported coefficients of variation ranging from 11.8% to 21.4% with a mean of 16%.

2) Roberts et al (1999), however, suggested that a homogenous unsaturated iron-binding capacity (UIBC) method (equivalent to the difference between the amount of iron added and the excess unbound iron measured) can provide reliable TIBC results. This method is NOT reliable when the iron concentration exceeds 500 micrograms/dL (underestimates TIBC value).

a) No methods of TIBC determination are useful in the presence of deferoxamine due to its ability to interfere with TIBC by providing falsely elevated TIBC values with increasing deferoxamine concentrations (TIBC measurements should be obtained 4 hours after the last administration of deferoxamine to limit any interference).

c) For low serum iron concentrations, the presence of free iron may be determined by obtaining serum iron and iron binding capacity. If serum iron exceeds the total iron binding capacity, free serum iron may be present.
d) Using an ion exchange resin or excessive amounts of magnesium carbonate to bind free iron may improve the accuracy of TIBC measurements in iron overdose patients (Yatscoff et al, 1991).
e) ANIMAL STUDY/DEFEROXAMINE - Bentur et al (1991) found that deferoxamine infusion in dogs falsely elevated laboratory measurements of TIBC. The magnitude of error was dependent on time after ingestion and time after deferoxamine administration.

2) SERUM IRON - Draw blood for serum iron determination into heparinized tubes before deferoxamine is administered to avoid a known drug-lab interaction.

a) The presence of the deferoxamine iron complex (ferrioxamine) may result in falsely low total serum iron values when assayed by some of the widely used analytical methods used to measure serum iron (Gervitz & Wasserman, 1966; (Wythe et al, 1986).

1) Its suggested that when available, serum iron concentrations should be monitored along with clinical signs and symptoms to effectively treat the overdosed patient (Roberts et al, 1999).
2) Serum iron concentrations should be measured by ATOMIC ABSORPTION SPECTROPHOTOMETRY, especially following therapy with deferoxamine in order to avoid this drug-lab interaction (Helfer & Rodgerson, 1966).
3) The addition of 0.5 mL of a 100 mL/L aqueous thioglycolic acid solution, when added to the standard ACA test packs, may remove the interference caused by deferoxamine in measuring serum iron levels (Wians et al, 1988). Hemolysis however may interfere with this technique.

3) URINE IRON - A method for measuring urine iron includes using thioglycolic acid and trichloroacetic acid to release iron from ferrioxamine and then a standard automated colorimetric procedure for the final measurement.

a) This method is not useful in patients with hemoglobin or myoglobin in the urine (Yatscoff et al, 1991).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who have hypotension, severe or worsening metabolic acidosis, GI hemorrhage, altered mental status, or a patient that requires chelation should be admitted.
B) Referral to a healthcare facility has been recommended for patients with an iron ingestion of greater than 40 mg/kg (Manoguerra et al, 2005; Klein-Schwartz et al, 1990).

6.3.1.2) HOME CRITERIA/ORAL

A) SUMMARY

1) Inadvertent ingestions of less than 40 mg/kg of elemental iron in patients with only mild GI symptoms (self limited vomiting or diarrhea) can be watched at home (Manoguerra et al, 2005).
2) Any patient developing severe symptoms (i.e., coma, hypotension, GI bleeding, protracted vomiting/diarrhea), and those with a deliberate overdose or ingesting 40 mg/kg or more should be referred to a healthcare facility (Manoguerra et al, 2005).

B) STUDIES

1) Retrospective evaluation of serious poisoning from children's chewable multivitamins was conducted. The review covered NDCS reports from 1985 to 1991, in which there were 74,601 exposures. There were a total of 35 major effects and no deaths reported.

a) During this same study period, 25,067 exposures to high potency adult formulations of iron were reported. There were a total of 125 major effects and 29 deaths (Anderson et al, 1993).

2) A review of the 1986-1988 AAPCC data on 54,168 iron poisoning cases revealed that multivitamins with iron accounted for 83% of total iron exposures, but only 11% of iron-induced mortality (Krenzelok, 1991).
3) Adults ingesting 20 mg/kg of iron, without GI decontamination, have developed moderate symptoms (Burkhart et al, 1991).

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings, and for recommendations on determining the need for chelation or whole bowel irrigation. Consult a gastroenterologist for endoscopic removal if many tablets persist in the stomach.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with more than mild symptoms, those who have ingested 40 mg/kg or more, or patients with intentional ingestions should be sent to a healthcare facility for evaluation (Manoguerra et al, 2005).

Monitoring

A)

B)

C)

D)

E)

Oral Exposure

6.5.1)

A) ACTIVATED CHARCOAL

1) Activated charcoal is not useful. Most patients have spontaneous vomiting.

6.5.2)

A) SUMMARY

1) Activated charcoal does not adequately bind iron and is not useful. Studies have suggested that magnesium hydroxide antacids (5 mg magnesium hydroxide per gram of elemental iron ingested) decrease serum iron concentrations following a simulated overdose. Gastric lavage may be useful soon after ingestion in adults, but the nasogastric tubes used in children are not sufficiently large to remove tablets. In patients with large amounts of radiopaque tablets in the GI tract, whole bowel irrigation with polyethylene glycol should be considered. Endoscopic removal is another option for patients with a large number of tablets in the stomach.
2) An abdominal x-ray should then be obtained to determine the need for further decontamination. A negative X-ray does not rule out the possibility of an iron ingestion or the presence of iron in the gastrointestinal tract (Ng et al, 1979). Tablets may be radiopaque. Multivitamin with iron tablets, however, contain less elemental iron and therefore may not produce the distinct radiodensities seen with prenatal iron. The KUB may demonstrate a more diffuse pattern.

B) GASTRIC LAVAGE

1) Gastric lavage is typically indicated up to one hour after ingestion. When slow-release or enteric-coated iron tablets are involved, or there is evidence of iron on abdominal radiographs, gastric lavage may be indicated for a longer period of time post-ingestion.
2) LAVAGE TUBE SIZE: Because the size of orogastric tube that can be passed in a small child may not be of sufficient diameter to remove tablets or large tablet fragments and because iron is not well adsorbed by activated charcoal, decontamination can be difficult. The use of a large lavage tube (32 to 40 French) has been recommended in adults (Blanc et al, 1984; Engle et al, 1987; Greengard, 1975; Oderda et al, 1987; Proudfoot et al, 1986) and 32 French in children as young as 15 to 24 months of age (Gandhi & Robarts, 1962; Schauben et al, 1990).
3) Lavage with bicarbonate solutions or deferoxamine is NOT recommended.
4) CASE REPORT: A 15 year-old girl ingested 20 slow release iron tablets, and 6 hours after ingestion a X-ray showed a conglomerate of iron tablets in the patient's stomach area. Gastric lavage was performed and successfully cleared the iron conglomerate (Goldstein & Berkovitch, 2006).
5) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

6) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

7) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

8) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

9) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

C) ABDOMINAL X-RAY PATTERNS

1) Tablets may remain in the gut and an abdominal X-ray should be obtained to determine if further lavage is necessary. As dissolution occurs, a diffuse density rather than discrete tablets may be seen.
2) Completely dissolved iron tablets/capsules may not be radiopaque (Jaeger et al, 1981; Ng et al, 1979). A positive abdominal radiograph is more likely to be associated with severe toxicity (James, 1970).
3) CASE SERIES: In a retrospective study of 93 pediatric patients who had ingested potentially toxic amounts of an iron supplement, only 1 of 30 patients had radiopaque densities that could be marginally visualized following an ingestion of a chewable iron supplement. The mean serum iron concentration was 270 mcg/dL in patients who had ingested a chewable iron supplement (Everson et al, 1989).

D) WHOLE BOWEL IRRIGATION (WBI)

1) INDICATIONS

a) WBI is indicated in patients with documented undissolved tablets past the pylorus or with a large quantity dispersed throughout the gastrointestinal tract or with persistent tablets in the stomach despite attempts at decontamination (Schauben et al, 1990; Bock & Tenenbein, 1987; Tenenbein, 1985a).

2) Whole bowel irrigation may successfully remove iron tablets from the gut in children, adolescents, and pregnant women without complications or significant electrolyte changes (Everson et al, 1991; Tenenbein & Yatscoff, 1991; Van Ameyde & Tenenbein, 1989; Schauben et al, 1990; Tenenbein, 1985).

a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.

1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.

b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.

4) CASE REPORT: The solution used successfully in a 16-year-old patient was GoLYTELY(R) infused down a nasogastric tube at 2 L/hour for 12 hours (Tenenbein, 1985a).
5) CASE REPORT: Whole bowel irrigation was used in a pregnant woman (38 weeks gestation) who ingested iron tablets, which were still visible in the stomach after orogastric lavage. No complications were reported (Van Ameyde & Tenenbein, 1989).
6) CASE REPORT: A 33-month-old male (15 kg) received 44 L of PEG over 121 hours at rates of 300-1000 mL/hour starting 15 hours after ingesting 160 mg/kg of elemental iron. Concurrent metoclopramide 0.1 mg/kg IV every 6 hours was given. WBI halted when X-ray revealed only 2 tablets remaining in distal colon. The patient tolerated the WBI without complications (Kaczorowski & Wax, 1994).

E) ENDOSCOPY

1) Endoscopic removal should be considered if WBI is ineffective and most of the pills are visible in the stomach on radiography.
2) CASE REPORT: A 45-year-old woman (50 kg) presented with gastrointestinal symptoms (nausea, vomiting, diarrhea) after ingesting 100 ferrous sulfate tablets (300 mg per tablet); approximate elemental iron ingestion was 120 mg/kg. After gastric lavage, repeat x-ray showed a radio-opaque conglomerate of tablets in the stomach's fundal region. Endoscopic removal was successfully performed to retrieve and break up a 5 cm mass of congealed tablets. The stomach was then irrigated with two liters of normal saline and remaining tablet particles aspirated. The patient made an uneventful recovery (Ng et al, 2008).
3) CASE REPORT: A 21-year-old man intentionally ingested 30 ferrous sulfate tablets (325 mg per tablet) and presented one hour later. Initial serum iron level was 246 mcg/dL, and abdominal x-ray showed a conglomerate of tablets in the gastric fundus. The bezoar of tablets persisted following gastric lavage, and endoscopic removal commenced. The iron pills were retrieved and broken up; followed by extensive irrigation and suction. After the endoscopy-directed lavage, serum iron levels normalized to 120 mcg/dL (Atiq et al, 2008).

F) SURGICAL THERAPY

1) Emergency gastrotomy should be considered in those patients when emesis, lavage, and whole bowel irrigation are unsuccessful in removing intact iron tablets from the stomach after massive overdose (Venturelli et al, 1982; Foxford & Goldfrank, 1985; Peterson & Fifield, 1980; Landsman et al, 1987).
2) LAPAROSCOPIC-ASSISTED GASTROTOMY: A 14-year-old girl ingested a large quantity of ferrous fumarate at a calculated potentially lethal dose of 70 mg/kg and presented 2 hours later with a Glasgow coma scale of 10. Her serum iron concentration was 65 mcmol/L (normal range, 5 to 27 mcmol/L) on presentation. In the PICU, she was administrated IV deferoxamine and a plain chest radiograph revealed a large radio-opaque mass in the stomach. Endoscopic view of the stomach revealed iron concretions smeared on the antral mucosa proximal to the pylorus. She underwent a laparoscopic-assisted gastrotomy and an iron bezoar was removed by digital disimpaction and copious saline irritation. After gastrotomy, her serum iron concentration decreased and she quickly recovered (Haider et al, 2009).
3) OTHER INDICATIONS FOR GASTROTOMY: Very large intragastric amounts of iron (greater than 100 mg/kg elemental iron) are found on radiograph; if a drug bezoar is suspected; or if there is evidence that iron is adhered to the gastric wall (Tenenbein & Yatscoff, 1991).

G) ANTACIDS

1) Magnesium hydroxide and calcium carbonate containing antacids may safely be used in therapeutic doses to help reduce iron absorption (O'Neil-Cutting & Crosby, 1986; Banner & Tong, 1986). In one randomized crossover study volunteers ingested 5 mg/kg elemental iron followed 1 hour later by 4.5 grams magnesium hydroxide per gram ingested iron (Wallace et al, 1998). Magnesium hydroxide significantly reduced iron absorption in the 12 hours following iron ingestion. In another randomized controlled trial administration of MgOH (5:1 ratio to elemental iron) did not affect iron absorption in humans after a supratherapeutic dose (10 mg/kg) of iron (Snyder & Clark, 1999).

H) NOT RECOMMENDED

1) ORAL COMPLEXATION: Oral administration of dilute sodium bicarbonate or Fleets Phosphosoda Enema to complex intragastric iron is NOT recommended.

a) IN VITRO bicarbonate and phosphate form relatively insoluble complexes with iron (Czajka et al, 1981), however in vivo they probably complex at best 15% of the available iron in the stomach.
b) Use of dilute phosphosoda in this setting has caused life threatening hypernatremia, hyperphosphatemia and hypocalcemia (Geffner & Opas, 1980). It would require repeated administration of sodium bicarbonate to maintain the gastric pH in the desired range to maintain complexation, with the inherent risk of hypernatremia.
c) ANIMAL: Studies in dogs, pigs, and rats have found no beneficial effects from oral administration of bicarbonate or phosphate in preventing iron absorption (Dean & Krenzelok, 1985; Dean et al, 1988; Dean & Krenzelok, 1987).

I) ACTIVATED CHARCOAL

1) Iron binds weakly to activated charcoal; it is generally NOT RECOMMENDED unless there are significant coingestants involved(Yonker et al, 1980; Decker et al, 1968).
2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

4) IN VITRO STUDY: The adsorptive capacity of activated charcoal for ferrous sulfate (a 1.49% ferrous sulfate stock solution was prepared with distilled water) was tested in 3 pH environments (pH = 1.5, 4.5, or 7.5). Simulated gastric fluid was prepared with the final pH of these 3 test solutions adjusted with hydrochloric acid or sodium hydroxide. At a pH of 4.5 or 7.5, activated charcoal had significant (p < 0.01) adsorptive capacity for iron as compared to the negligible amount at a pH of 1.5. An alkaline pH environment promoted formation of insoluble iron complexes, which may have indicated some reduction in iron solubility. The authors suggested further in vivo studies (Chyka et al, 2000).
5) IN VIVO STUDY: A study was conducted with male Sprague-Dawley rats (a total of 53 completed the study) to determine whether activated charcoal altered the gastrointestinal absorption of toxic doses of iron as ferrous sulfate. The rats were randomized to one of five groups, and given the following treatments: (1) control given only 3 mL of distilled water; (2) 100 mg elemental iron + 1 mL distilled water; (3) 1:1 ratio of activated charcoal to iron (100 mg elemental iron + 100 mg activated charcoal); (4) 2:1 ratio of activated charcoal to iron; and (5) 4:1 ratio of activated charcoal to iron. Across the 4 treatment groups, mean serum iron concentrations did not differ at the various sampling times (ie, 1 hour, 4 hours, and 8 hours after iron administration), except at 1 hour for groups 4 {serum iron concentration 737) and 5 {serum iron concentration 1251}. The results indicated that activated charcoal did not alter iron absorption into the bloodstream. The authors suggested this study did not support earlier in vitro reports of the potential benefits of activated charcoal to limit ferrous sulfate absorption from the gastrointestinal tract (Gades et al, 2003).
6) The iron-deferoxamine complex has also been shown to have some affinity for charcoal (Yonker et al, 1980).
7) DEFEROXAMINE/CHARCOAL SLURRY: A prospective, crossover study in healthy volunteers found that an oral slurry of deferoxamine mesylate (DFO) and activated charcoal (AC) reduced the GI absorption of ferrous sulfate (Gomez et al, 1997).

a) Prior studies indicated that AC could adsorb iron from solutions that contain DFO. A premixed 1:3 (weight/weight) DFO (8 grams)/AC (25 grams of 20% weight/volume) slurry was given to volunteers (a previous in vitro study determined that ferrioxamine was maximally bound to AC at this ratio).
b) AUC (p = 0.042) and Cmax (p = 0.017) were significantly lower in all subjects given the slurry versus the control limbs; Tmax iron concentration was not significantly affected.
c) The combination of oral deferoxamine and activated charcoal has not been studied in poisoned patients and it is not recommended for routine clinical use at this time.

8) ANIMAL DATA: In a rat model, male and female rats were given iron sulfate at a dose of 200 mg/kg. The effects of activated charcoal (AC) and deferoxamine (DFO) with or without sodium bicarbonate were analyzed to determine if iron absorption was reduced from the digestive tract. An oral slurry of AC (100 mg/mL and 200 mg/mL) was given at a dose of 500 and 1000 mg/kg, along with a 75 mg/mL suspension of DFO given at a dose of 150 mg/kg. The coadministration of sodium bicarbonate also occurred.

a) RESULTS: The findings revealed that oral dosing with DFO and AC (separately and simultaneously, immediately or 10 to 20 minutes after dosing) did NOT prevent iron absorption from the digestive tract. However, DFO significantly decreased the elevated serum iron concentrations, presumably by chelating the already absorbed iron; sodium bicarbonate seemed to enhance this effect. Coadministration of sodium bicarbonate further decreased serum iron concentrations at 3, 5, and 6 hours after iron administration. When given alone, AC had NO effect on iron absorption (Eshel et al, 2000).
b) In another study using male rats only, AC was also found to NOT alter the extent of iron absorption (Gades et al, 2000).

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Supportive care with intravenous fluid hydration is usually sufficient for mild poisonings. Activated charcoal is not effective for iron ingestions. Patients who are symptomatic should be observed for clinical deterioration and development of acidosis. Abdominal x-rays should be obtained as tablets are generally radiopaque. When large amounts of tablets are visible on radiograph, consider whole bowel irrigation. An iron concentration should be measured 4 to 6 hours after the initial ingestion and then repeated in 2 to 4 hours. Patients who develop metabolic acidosis or are clinically worsening with IV hydration should be treated with chelation.

2) MANAGEMENT OF SEVERE TOXICITY

a) Chelation with deferoxamine is needed for patients with signs of severe poisoning including shock, acidosis, GI hemorrhage, and lethargy or coma. Consider chelation for serum iron concentrations greater than 500 mcg/dL (a patient will usually have significant signs and symptoms of toxicity). Patients may need blood transfusions if they have significant GI hemorrhage.

B) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Serial serum iron levels are indicated.
3) Obtain a complete metabolic panel and complete blood count.
4) Baseline arterial or venous blood gas in patients with severe toxicity.
5) Obtain an abdominal radiograph to evaluate for retained tablets.

C) ASYMPTOMATIC

1) ASYMPTOMATIC PATIENT

a) Decontamination is recommended if greater than 40 mg/kg of elemental iron has been ingested or if the amount ingested is unknown. Decontamination efficacy should be monitored by following serial KUBs until no tablets are seen.

1) NEGATIVE KUB: Observe patient for 6 hours; if no symptoms develop (minor or major) then toxicity is unlikely and no further follow-up is necessary (Lacouture et al, 1981).
2) As dissolution occurs, a diffuse density rather than discrete tablets MAY be seen. Completely dissolved iron tablets/capsules may not be radiopaque (Jaeger et al, 1981).
3) POSITIVE KUB: Evacuate gastric contents again and repeat x-ray. Determine CBC, blood sugar, electrolytes, and serum iron.
4) Blood should be drawn into a heparinized tube for determination of serum iron. Deferoxamine interferes with many laboratory determinations of serum iron resulting in falsely low values (see Laboratory Section).
5) When possible, determine serum iron before initiating deferoxamine therapy.

b) Institute DEFEROXAMINE THERAPY if the patient becomes symptomatic (more than transient nausea/vomiting, diarrhea, lethargy, hypotension, bloody emesis or diarrhea) or acidotic. Consider deferoxamine if peak serum iron is greater than 350 to 500 mcg/dL (most patients with serum iron in this range are symptomatic). Peak serum iron level is usually between 3 to 6 hours post-ingestion.

1) Peak may be delayed with enteric-coated products or in cases of bezoar formation.

2) SYMPTOMATIC PATIENT

a) Evacuate stomach promptly. Obtain abdominal and chest x-ray to evaluate for residual tablets. If tablets remain in the stomach evacuate stomach again and repeat X-ray. If tablets persist in the stomach or are visible beyond the pylorus, begin whole bowel irrigation.

1) NOTE: As dissolution occurs, a diffuse density rather than discrete tablets may be seen. Completely dissolved iron tablets/capsules may not be radiopaque (Jaeger et al, 1981).

b) DETERMINE SERUM IRON, CBC, ELECTROLYTES, AND BLOOD GLUCOSE

1) Blood should be drawn into red top or heparinized tubes (consult laboratory for specific recommendations) for determination of serum iron.
2) Deferoxamine interferes with many laboratory determinations of serum iron resulting in falsely low values (see Laboratory Section). When possible, determine serum iron before initiating deferoxamine therapy.
3) The best time to draw a serum level(s) postingestion is unknown. Absorptive and distribution variations have made it difficult to produce reliable curves or estimate time of peak levels.
4) As a guideline, most authorities recommend obtaining an initial level at 3 to 4 hours for liquid or coated tablet formulations (Tong & Banner, 1986; Bayer & Rumack, 1983).
5) Peak absorption probably does not occur sooner than 1 to 2 hours or later than 6 hours. SUSTAINED-RELEASE or ENTERIC-COATED preparations have extremely erratic kinetics.
6) It may be best to draw 2 or more levels, 3 to 4 hours postingestion, and again at 6 to 8 hours postingestion.
7) Institute DEFEROXAMINE THERAPY in any symptomatic patient (more than transient nausea/vomiting, diarrhea, lethargy, hypotension, bloody emesis or diarrhea) or acidotic. Consider deferoxamine if peak serum iron is greater than 350 to 500 mcg/dL (most patients with serum iron in this range are symptomatic). Peak is usually between 3 to 6 hours postingestion.

a) Peak may be delayed with enteric-coated products or in cases of bezoar formation.

D) HYPOTENSIVE EPISODE

1) Institute life support measures; correct electrolyte balance, treat shock with fluids or whole blood; support respirations; monitor blood sugar carefully (rule out hypoglycemia) and correct coagulopathy.
2) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

3) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

4) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

E) DEFEROXAMINE

1) DEFEROXAMINE INDICATIONS: Institute intravenous deferoxamine chelation therapy in any patient with signs and/or symptoms of significant iron poisoning including lethargy, coma, hypotension, severe persistent vomiting and diarrhea, shock or metabolic acidosis. Transient nausea and vomiting occurring immediately after ingestion, that resolves without therapy, generally does not warrant treatment in the absence of other symptoms or laboratory abnormalities (Tenenbein, 1996).
2) Chelation should also be considered in patients with peak serum iron concentrations of 500 mcg/dL or more; the vast majority of these patients will have clinical evidence of iron poisoning (Tenenbein, 1996).
3) EFFICACY

a) Deferoxamine binds 8.5 mg of elemental iron per 100 mg of the chelate.
b) In thalassemic patients 750 mg of deferoxamine intramuscularly bound 15 mg of iron, while intravenously, given over 24 hours it bound 50 mg of iron (Lovejoy, 1983; Lovejoy, 1982).

4) DOSING

a) ACUTE IRON INTOXICATION

1) ADULT DOSE: Administer deferoxamine by continuous IV infusion at a rate of 15 mg/kg/hour. It can be titrated up to a rate of 40 mg/kg/hour for patients with life-threatening iron toxicity, although hypotension may occur with higher doses, and the rate should be decreased if this develops (Seifert, 2004).
2) PEDIATRIC DOSE: Administer deferoxamine by continuous IV infusion at a rate of 15 mg/kg/hour (Seifert, 2004). Infusion rates up to 35 mg/kg/hour have been used in children with severe overdoses without adverse effects (Boehnert et al, 1985), although hypotension may occur with higher doses, and the rate should be decreased if this develops (Seifert, 2004).
3) PATIENTS IN SHOCK: Correct intravascular volume depletion to avoid further hypotension induced by deferoxamine.

b) DURATION OF INFUSION

1) Duration of infusion is generally 12 hours in patients with moderate poisoning, up to 24 hours in patients with severe poisoning. The patient should be titrated off the infusion if clinically improving. If the patient worsens as the deferoxamine is titrated off, it should be restarted. Infusions of greater than 24 hours have been associated with acute lung injury and should be avoided (Seifert, 2004; Tenenbein et al, 1992).
2) CASE SERIES: Severe or fatal pulmonary toxicity developed in 8 of 14 patients who received infusions of longer than 24 hours. Pulmonary toxicity did not develop in 29 patients treated for less than 24 hours (Tenenbein et al, 1992a).
3) OTHER ROUTES OF ADMINISTRATION

a) Gastric lavage with deferoxamine solution is NOT RECOMMENDED. Intramuscular administration is NOT RECOMMENDED in patients with acute iron overdose.

c) DURATION OF THERAPY

1) Duration of infusion is 12 hours in patients with moderate poisoning, up to 24 hours in patients with severe poisoning. The patient should be titrated off the infusion if clinically improving. If the patient worsens as the deferoxamine is titrated off, it should be restarted. Infusions of greater than 24 hours have been associated with acute lung injury and should be avoided (Seifert, 2004; Howland, 1996).

d) VIN ROSE TEST

1) Pink to orange-red urine indicates excretion of ferrioxamine (chelated iron), although frequently urine color change does not occur (Freeman & Manoguerra, 1981; Oderda et al, 1987a; Harchelroad & Rice, 1992).
2) Loss of the 'vin rose' color may be used as an endpoint for deferoxamine therapy. However, because the color is concentration dependent, absence of color does not necessarily suggest the absence of the chelant or ferriuresis (Yatscoff et al, 1991).

5) ADVERSE EFFECTS

a) PULMONARY TOXICITY

1) Adult respiratory distress syndrome has been reported in patients receiving prolonged high dose infusions (15 milligrams/kilogram/hour for 45 to 98 hours) for acute iron poisoning (Tenenbein et al, 1992). Severe or fatal pulmonary toxicity developed in 8 of 14 patients who received infusions of longer than 24 hours. Pulmonary toxicity did not develop in 29 patients treated for less than 24 hours (Tenenbein et al, 1992).
2) A "pulmonary syndrome" has been associated with high dose intravenous (10 to 25 milligrams/kilogram/hour) deferoxamine therapy for several days for acute and chronic iron overload patients; features can include tachypnea, dyspnea, hypoxemia, cyanosis, fever, eosinophilia, preceding urticaria, and/or interstitial infiltrates (Ioannides & Panisello, 2000; Freedman et al, 1990; Scanderbeg et al, 1990; Benson & Cheney, 1992a; Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).

a) ONSET: usually 3 to 9 days after initiating deferoxamine therapy (Anderson & Rivers, 1992).

3) Pulmonary toxicity may be related to the duration of infusion and high daily doses (Macarol & Yawalkar, 1992).

b) SEPSIS

1) The use of deferoxamine in patients with acute iron overdose or chronic iron overload has been associated with Yersinia enterocolitica septicemia, and with mucormycosis in chronic iron overloaded patients (Boelaert et al, 1993; Melby et al, 1982a).
2) Deferoxamine may have provided the iron siderophore growth factor required by the bacteria Yersinia and the fungus Rhizopus (Boelaert et al, 1993).

c) VISUAL AND AUDITORY TOXICITY

1) Impaired color vision, bilateral scotomas, night blindness, decreased visual acuity and retinal pigmentation have been reported in patients receiving chronic deferoxamine treatment (Bene et al, 1989; Pengloan et al, 1987; Olivieri et al, 1986; Blake et al, 1985; Davies et al, 1983). Cataracts, retinal abnormalities and night blindness have been reported (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012; Yokel, 1994).
2) Hearing disturbances have been reported, including tinnitus and hearing loss (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).

d) HIGH-DOSE DEFEROXAMINE: A 22-year-old woman with an extremely high serum iron concentration (4573 mcg/dL) after ingesting 180 tablets of 300 mg ferrous sulfate (216 mg/kg elemental iron), received high-dose IV deferoxamine (15 mg/kg/hr started 8 hours after ingestion, increased to 30 mg/kg/hr 2 hours later, and then decreased to 15 mg/kg/hr 4 hours later). Despite severe gastrointestinal complications and metabolic acidosis, she rapidly recovered following supportive care and did not developed any adverse effects from high-dose deferoxamine (Noble et al, 2015).

6) PREGNANCY

a) PREGNANCY RECOMMENDATION

1) Based on case reports which have suggested benefit to the maternal patient and no adverse effects on fetuses, it is recommended that deferoxamine treatment not be withheld from pregnant patients (Singer & Vichinsky, 1999a).
2) Deferoxamine is pregnancy category C (Prod Info deferoxamine mesylate subcutaneous injection, intramuscular injection, intravenous injection, 2012).

b) HUMAN DATA

1) Of 25 pregnant iron overdose patients treated with deferoxamine, 20 (80%) delivered healthy full-term babies. Six patients had serum levels of greater than or equal to 90 micromoles/liter, and all six delivered healthy full-term babies after gastric decontamination and deferoxamine therapy (McElhatton et al, 1991a).
2) A review of published cases of iron poisoning in pregnant women found that women who developed end organ damage secondary to iron overdose were more likely to suffer spontaneous abortion, preterm delivery and maternal death than patients who did not develop end organ damage (Tran et al, 2000).

c) ANIMAL DATA

1) Fetal serum iron concentrations did not change significantly when deferoxamine was infused intravenously into pregnant ewes (third stage of gestation) (Curry et al, 1990a).
2) No measurable deferoxamine or ferrioxamine was detected in fetal blood up to 4 hours following intravenous administration to pregnant ewes (Curry et al, 1990a).

d) CASE REPORT: A 27-year-old, at 27 weeks gestation, ingested 24 mg/kg of elemental iron and had an initial serum iron level of 603 mcg/dL (normal range 50-170 mcg/dL). Chelation therapy included deferoxamine started at 1 gram/hour (15 mg/kg/hour) and was continued for 2 hours; ferritin levels dropped to normal within 48 hours. At 32 weeks, a 2420 gram infant with normal Apgar scores was delivered. The infant was discharged to home on day 7 with no further follow-up reported (Tran et al, 1998).
e) CASE REPORT/CHRONIC THERAPY: An 18-year-old with a history of thalassemia, chronic hepatitis, and iron overload became pregnant and stopped her DFO therapy. By 16 weeks gestation her ferritin level had reached 6000 ng/mL. At 18 weeks gestation DFO was restarted at a dose of 40 mg/kg via SQ infusion 4 days/week and intravenous treatment of 50 mg/kg every 2 weeks. At 26 weeks, the subcutaneous dose was increased to 50 mg/kg/day and intravenous dose to 80 mg/kg. A MediPort was inserted at 30 weeks to administer DFO at 50 mg/kg/day. The patient gave birth at 38 weeks gestation. At 10 month follow-up, the child was developmentally age-appropriate, and evaluation for DFO toxicity (ie, audiogram, skeletal survey for bone dysplasia, and ophthalmology exam) was negative (Singer & Vichinsky, 1999).

F) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

G) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

H) TRANSPLANTATION OF LIVER

1) Fulminant hepatic failure, requiring liver transplantation, has been reported in several patients after iron overdose (Fil et al, 2015; Comes et al, 1993; Taalikka et al, 1999).

I) EXPERIMENTAL THERAPY

1) DEFEROXAMINE CONJUGATES: Deferoxamine conjugated to dextran or hydroxyethylstarch did not produce hypotension and persisted longer than free deferoxamine (Mahoney et al, 1989). These conjugates improved survival and prevented hepatotoxicity in a mouse model.
2) PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE (PS-ODNs) is a synthetic nucleotide used for chemotherapy and may have potential for use as a heavy metal chelator including iron. PS-ODNs are modified DNA molecules with sulfur replacing nonbinding oxygen on the phosphate backbone, which creates a stable poly-anionic molecule. In vitro studies indicate that it binds iron.

a) Iron excretion was measured in 16 patients receiving PS-ODNs, with a history of relapsed or refractory acute myelogenous leukemia or myelodysplastic syndrome. Doses were given for 10 days by continuous intravenous infusion with adverse effects monitored. Urinary iron excretion increased by 7.5 fold during therapy. The authors suggested that PS-ODNs may have a therapeutic role as a heavy metal chelator (Angle et al, 2000).

3) ORAL CHELATORS

a) Oral iron chelators have not been used to treat acute iron overdose. They should be considered in patients with recent, large ingestions in whom maximal deferoxamine therapy may not be sufficient.
b) DEFERASIROX: In a double-blind, placebo-controlled, randomized, crossover study, deferasirox, an oral chelator used for chronic iron overload, was found to significantly reduce serum irons levels when administered 1 hour after an acute iron ingestion of 5 mg/kg of elemental iron in 8 healthy volunteers. Baseline serum iron concentrations were similar between the 2 groups. The treatment group received 20 mg/kg of deferasirox 1 hour after the acute iron ingestion. The primary endpoints were area under the iron concentration-time curve from baseline to 12 hours and from baseline to 24 hours. Significant differences were observed between the placebo and treatment groups for the area under the iron concentration curve at 1 to 12 hours (577 mcmol-hr/L and 392 mcmol-hr/L {difference 185 mcmol-hr/L}, 95% confidence interval (CI) for the difference of 15.8 to 353 mcmol-hr/L) and at 1 to 24 hours (808 mcmol-hr/L and 598 mcmol-hour/L {difference 210 mcmol-hr/L}, 95% CI for the difference of 54.4 to 366.7 mcmol-hr/L), respectively (Griffith et al, 2011).
c) HYDROXPYRIDONE CHELATORS: Hydroxpyridone chelators such as 1,2-dimethyl-3-hydroxypyrid-4-one (deferiprone) are currently being investigated for the treatment of chronic iron-overloaded patients (Olivieri et al, 1990; Richardson & Ponka, 1998).

1) This agent was shown to be effective in removing iron in cases of beta-thalassemia and myelodysplasia. It was more effective when given with ascorbic acid (Kontoghiorghes et al, 1987).
2) In subchronic (3 month) toxicity studies in animals, Berdoukas et al (1993) reported 1,2-dimethyl-3-hydroxypyrid-4-one (deferiprone) to be toxic to proliferating tissues, especially the bone marrow. Deferiprone may have serious side effects including agranulocytosis, neutropenia, arthropathy, GI disorders, zinc deficiency, and fluctuations in liver function (Berdoukas et al, 1993; Hoffbrand & Wonke, 1997; Diav-Citrin & Koren , 1997; Kowdley, 1998).

d) PYRIDOXAL ISONICOTINOYL HYDRAZONE (PHI) is a tridentate chelator. In studies of thalassemic patients dosed at 30 mg/kg/day, a net iron excretion of approximately 0.12 mg/kg/day was seen. This value is much less than the desired 0.5 mg/kg/day iron excretion typically needed to obtain a negative iron balance in this patient population, but it has been argued PHI's iron excretion ability may be sufficient for patients who are not transfusion dependent. More studies are necessary to determine PHI's therapeutic potential (Hershko et al, 2005).
e) BIS-HYDROXYPHENYL-TIRAZOLE is a new class of tridentate iron-selective synthetic chelators. One compound in this class (ICL670) has shown efficacy as a once daily oral option for iron overload. Clinical trials involving 63 patients demonstrated a decrease of 1.5 mg iron/gram dry liver weight after 6 months of therapy at a dose of 20 mg/kg/day. This decrease in iron is equivalent to that seen with standard dosing of parenteral deferoxamine 40 mg/kg/day. More studies are necessary to determine ICL670's therapeutic potential (Hershko et al, 2005).

4) DEFERIPRONE

a) ANIMAL STUDIES

1) Berkovitch et al (2000) studied the effects of orally administered deferiprone on rats given 612 mg/kg elemental iron orally (equivalent to the LD50 in this species). Two groups of rats received oral deferiprone at 800 mg/kg with one of the groups receiving a repeat dose 2 hours later. The results indicated that coadministration of 800 mg/kg deferiprone with iron decreased mortality from 30% to 6.6% after 2 hours, 40% to 16.6% after 12 hours, and from 53.3% to 20% after 24 hours (Berkovitch et al, 2000).

a) Mortality was also significantly decreased among rats given 2 repeated doses of deferiprone from 0%, 9%, and 18% at 2, 12, and 24 hours post iron administration, respectively. The findings indicated that morbidity and mortality were significantly reduced following deferiprone administration (Berkovitch et al, 2000).

2) DEFERIPRONE and SODIUM BICARBONATE: Barr et al (1999) also examined rats after receiving elemental iron (20 mg/kg) and sodium bicarbonate (1 mEq/kg) followed by immediate deferiprone treatment and another group receiving treatment 15 minutes after exposure. Serial iron levels indicated that deferiprone significantly reduced serum iron levels, but the effectiveness was delayed in the group receiving deferiprone 15 minutes after iron dosing (Barr et al, 1999).
3) LACK OF EFFECT: Hung et al (1997) found that in female Swiss albino mice with iron poisoning, deferiprone failed to decrease iron induced toxicity and appeared to increase mortality when compared to controls. The safety of a premixed deferiprone-iron mixture was examined and found to be nontoxic at doses up to 6 micromoles/gram iron and 18 micromoles/gram deferiprone; however deferiprone given alone was toxic at doses greater than 9 micromoles/gram (Hung et al, 1997).

b) HUMAN STUDIES

1) CHRONIC THERAPY: Olivieri et al (1998) examined the long-term safety of oral deferiprone in patients with thalassemia major and found that deferiprone did not adequately control body iron burden as evidenced by elevated hepatic iron concentrations (annual liver-biopsies were completed) and may worsen hepatic fibrosis (Olivieri et al, 1998).

a) Several authors, however, question the interpretation of the histological evidence and suggested that progression of hepatic fibrosis was not present (Tricta & Spino, 1998; Callea, 1998).
b) Of patients receiving deferiprone therapy, elevated liver function tests have been most frequently reported in patients infected with hepatitis C. During chronic therapy the raised serum transaminase levels gradually settled to pretreatment levels or lower after 3 months of therapy. An increase in ALT levels has also been reported in some patients receiving deferiprone therapy. Symptoms were considered to be mild and transient and resolved with cessation of therapy (Diav-Citrin & Koren , 1997).
c) Another small study conducted by Stella et al (1998) examined 20 patients with thalassemia major with half being treated with deferiprone, and found NO statistically significant difference between liver-biopsy results of those treated with deferiprone or deferoxamine. The authors suggested that deferiprone may NOT cause the progression of liver damage (Stella et al, 1998).

2) MULTICENTRE STUDY: A prospective open-label one year study of deferiprone was conducted to evaluate the incidence of adverse events. 187 patients (ranging in age from 10 to 41 years) were enrolled in the trial. Seventy-four patients (40%) had previously undergone splenectomy, and 142 (76%) were seropositive for hepatitis C. A daily dose of 25 mg/kg body weight was given three times daily for a total daily dose of 75 mg/kg deferiprone; with the dose adjusted as needed (Cohen et al, 2000).

a) ADVERSE EVENTS: The most frequently reported adverse event was reddish discoloration of the urine which was attributable to the excretion of the iron-deferiprone complex. Gastrointestinal symptoms (nausea and vomiting) were the next most common and usually resolved after the first few weeks of therapy without a change in the drug regimen. Arthropathy (13%) was not uncommon, and was more likely to occur with a higher ferritin level. The mean alanine transaminase (ALT) levels were significantly higher than baseline for all patients that completed the study. Agranulocytosis and milder forms of neutropenia were reported at rates of 0.6/100 and 5.4/100 patient years, respectively. This rate was lower than previously reported. Hematologic disorders resolved with drug cessation (Cohen et al, 2000).
b) SECONDARY OUTCOME: This study noted that individuals with the highest initial ferritin levels had the most significant decline (Cohen et al, 2000).

c) SUMMARY

1) It has been suggested that deferiprone can effectively reduce iron levels in most patients using the existing dosing protocols (ie, deferiprone 75 to 120 mg/kg/day), but further study is required to determine the optimal deferiprone dose(Kontoghiorghes et al, 2001). In most dose-response studies, a dose of 75 mg/kg body weight was the minimal daily dose required to achieve a negative iron balance in patients with thalassemia major (Diav-Citrin & Koren , 1997).
2) At the time of this review, the use of this agent remains uncertain for acute and chronic exposure.

5) OTHER/CHRONIC TOXICITY: Animal studies conducted in rats and primates indicated that subcutaneous injection of N,N-bis(2-hydroxybenzyl)ethylenediamine-N, N-diacetic acid (HBED) was an effective alternative to deferoxamine for the chronic treatment of transfusional iron overload (Bergeron et al, 1998).

Eye Exposure

6.8.2)

A) DEFEROXAMINE

1) Corneal rust rings around the foreign body are usually absorbed or sloughed off by phagocytic pathways and softening of the surrounding cornea. Treating with deferoxamine several times a day as eyedrops or 10% ophthalmic ointment can help in ridding these rings. They can also be removed mechanically or surgically by those trained in this procedure (Grant & Schuman, 1993).

B) SIDEROSIS OF EYE

1) Glaucoma associated with ocular siderosis may be responsive to carbonic anhydrase inhibitors but not the usual treatments for glaucoma (Grant & Schuman, 1993).

C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

A)

1) Consider exchange transfusion in those patients with a serum iron exceeding 1000 mcg/dL who clinically deteriorate despite supportive care and intravenous chelation therapy.
2) CASE REPORT: An 18-month-old girl (12 kg) presented to the emergency department after the ingestion of 5300 mg of iron (442 mg of elemental iron/kg; serum iron concentration 447 mcg/dL on admission). Despite standard therapy (gastric lavage, whole bowel irrigation, and intravenous deferoxamine) for 2 hours, her serum iron increased to 1362 mcg/dL (244 mcmol/L). Exchange transfusion (ET) 9 hours postingestion reduced serum iron to 134 mcg/dL (24 mcmol/L). Her serum iron level decreased further to 40 mcg/dL (7 mcmol/L) after plasmapheresis for 5 hours. She was extubated 18 hours after ET (Carlsson et al, 2008). The authors suggested that ET should be started within 12 hours of ingestion if possible. They also concluded that plasmapheresis after ET was unnecessary in this patient.
3) In one study performed in dogs, the amount of iron removed by exchange transfusion was much greater than that removed by deferoxamine (Movassaghi et al, 1969).

B)

1) CASE REPORT: An 18-month-old boy (weight 11 kg) presented with diarrhea and vomiting after ingesting about 1625 mg (147 mg/kg) of ferrous sulfate. He later became drowsy, requiring intubation and ventilation. X-ray of the abdomen revealed 13 tablet fragments. Despite standard therapy (gastric lavage, whole bowel irrigation, and intravenous deferoxamine 15 mg/kg/hr, total at least 360 mg/kg in 24 hours), his serum iron concentration increased to 700 mcmol/L (3906 mcg/dL) 6 hours after ingestion. He developed elevated ALT (359 Units/L) and coagulopathy with kaolin partial thromboplastin time at 74.5 s and prothrombin time at 16.5 s, requiring vitamin K, fresh frozen plasma, and cryoprecipitate. Approximately 14 hours postingestion, he underwent continuous veno-venous hemofiltration (CVVH) for 17 hours and his serum iron concentration quickly decreased to 24.5 mcmol/L (137 mcg/dL). Despite signs of organ damage, he gradually recovered and was discharged on day 5 (Milne & Petros, 2010).
2) CASE REPORT: An 18-year-old woman presented with persistent vomiting, abdominal pain, lethargy, altered mental status, tachycardia (124 beats/min), and severe anion gap metabolic acidosis about 8 hours after ingesting 50 ferrous sulfate tablets (100 mg of elemental iron per 335 mg tablet; 100 mg/kg of elemental iron). Following supportive care, including gastric lavage, whole bowel irrigation, continuous renal replacement therapies, continuous venovenous hemodiafiltration (dialysate rate: 1000 mL/hr, replacement rate: 1000 mL/hr, blood flow rate 100 to 150 mL/hr, and ultrafiltration rate 0 mL/hr), and deferoxamine therapy (10 to 15 mg/kg/hr IV continuous rate), her condition gradually improved. Her serum iron concentration decreased from 2150 to 160 mcg/dL (reference range: 40 to 150 mcg/dL) 24 hours after ingestion (Gumber et al, 2013).
3) In a dog model of iron intoxication, continuous arteriovenous hemofiltration (CAVH) was performed with deferoxamine administered by the arterial port. CAVH removed the iron-deferoxamine complex but not free iron (Banner et al, 1989).
4) The efficiency of total iron removal was less than predicted because significant amounts of deferoxamine were removed without bound iron, probably because insufficient mixing in the arterial line limited the formation of ferrioxamine.

C)

1) Deferoxamine administered 30 minutes before and during hemodialysis did not enhance the net removal of iron in chronically iron-overloaded patients undergoing dialysis (Roxe et al, 1990).

Abstracts

Case Reports

A)

1) A 3-year-old girl ingested an unknown number of 325 mg ferrous sulfate tablets. Initial labs taken at 6 hours revealed a serum iron level of 21,680 mcg/dL. Therapy included endotracheal intubation, copious IV fluids, whole bowel irrigation (up to 500 mL/hour) and deferoxamine (up to 30 mg/kg/hour). The patient developed fulminant hepatic failure, coagulopathy (PT peak 54 sec), GI bleeding, and hypoglycemia. Coagulopathy could not be corrected. On hospital day 3, AST and ALT peaked at 11,060 and 7,140 International Units/L. On hospital day 6, liver transplant was successfully performed with patient surviving (Comes et al, 1993).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) ELEMENTAL IRON

1) IV SOLUTION: The usual recommended dose is 100 mg to 400 mg of iron sucrose (Venofer(R)) diluted in a maximum of 100 mL or 250 mL NS, administered by slow IV injection or infusion, with a total cumulative dose of 1000 mg of elemental iron administered over sequential sessions. NOTE: 10 mL single-use vial of this product contains 200 mg elemental iron (20 mg/mL); 5 mL single-use vial contains 100 mg elemental iron (20 mg/mL); 2.5 mL single-use vial contains 50 mg elemental iron (20 mg/mL) (Prod Info Venofer(R) intravenous injection solution, 2012).
2) ORAL CAPSULES: The usual recommended dose is 150 mg to 300 mg of elemental iron daily (Prod Info FERREX 150 oral capsules, 2003).
3) ORAL ELIXIR: The usual recommended dose is 100 mg to 200 mg of elemental iron daily (Prod Info NIFEREX(R) oral elixir, 2005).
4) ORAL EXTENDED-RELEASE TABLETS: The usual recommended dose is 50 to 100 mg of elemental iron daily. MAXIMUM: 200 mg daily (Prod Info SLOW RELEASE IRON oral tablets, 2007).
5) The usual oral dose of elemental iron is 2 to 3 mg/kg/day in divided doses (Camitta & Nathan, 1975).

B) FERRIC CITRATE

1) ORAL TABLETS: The recommended initial dose is 2 tablets (1 g of ferric citrate/tablet or 210 mg ferric iron/tablet) 3 times daily. May be titrated by 1 to 2 tablets daily in 1-week or longer intervals. MAXIMUM 12 tablets daily (Prod Info Auryxia(TM) oral tablets, 2014).

C) FERRIC PYROPHOSPHATE CITRATE

1) SOLUTION: The usual recommended dose is one 5-mL ampule (each ampule contains 27.2 mg iron (III) per 5 mL; 5.44 mg of iron (III) per mL) in 2.5 gallons (9.46 L) of bicarbonate concentrate or one 50-mL ampule (each ampule contains 272 mg iron (III) per 50 mL; 5.44 mg of iron (III) per mL) in 25 gallons (94.6 L) of bicarbonate concentrate; final iron (III) dialysate concentration will be 2 micromolar (110 mcg iron (III)/L); administer at each hemodialysis session (Prod Info TRIFERIC(R) not applicable solution, 2015).
2) POWDER FOR SOLUTION: The usual recommended dose is 1 packet (each packet contains 272 mg iron (III)) in 25 gallons (94.6 L) of bicarbonate concentrate; final iron (III) dialysate concentration will be 2 micromolar (110 mcg iron (III)/L); administer at each hemodialysis session (Prod Info TRIFERIC(R) not applicable solution, 2015).

7.2.2)

A) ELEMENTAL IRON

1) GENERAL DOSING

a) ONE MONTH TO 12 MONTHS: 1 mg/kg/day to 2 mg/kg/day elemental iron, up to 15 mg elemental iron/day(Briefel et al, 2006; Prod Info Enfamil(R) Fer-In-Sol(R) oral drops, 2011).

2) IV SOLUTION

a) 2 YEARS AND OLDER: The usual recommended dose is 0.5 mg/kg of iron sucrose (Venofer(R)), not to exceed 100 mg/dose, every 2 or 4 weeks for 12 weeks administered undiluted by slow IV injection over 5 minutes or diluted in 25 mL of NS and administered over 5 to 60 minutes. NOTE: 10 mL single-use vial of this product contains 200 mg elemental iron (20 mg/mL); 5 mL single-use vial contains 100 mg elemental iron (20 mg/mL); 2.5 mL single-use vial contains 50 mg elemental iron (20 mg/mL) (Prod Info Venofer(R) intravenous injection solution, 2012).

3) ORAL ELIXIR

a) 12 TO 18 YEARS OF AGE: The usual recommended dose is 100 mg to 200 mg of elemental iron daily (Prod Info NIFEREX(R) oral elixir, 2005).
b) 6 TO 12 YEARS OF AGE: The usual recommended dose is 100 mg of elemental iron daily (Prod Info NIFEREX(R) oral elixir, 2005).

B) FERRIC CITRATE

1) ORAL TABLETS: Safety and efficacy of ferric citrate in the pediatric population have not been established (Prod Info Auryxia(TM) oral tablets, 2014).

C) FERRIC PYROPHOSPHATE CITRATE

1) Safety and effectiveness have not been established in pediatric patients (Prod Info TRIFERIC(R) not applicable solution, 2015).

Minimum Lethal Exposure

A)

1) Fatalities have occurred following pediatric ingestions of 1200 mg to 4500 mg of elemental iron.
2) Adult fatalities have been reported when only supportive care was provided or deferoxamine treatment was delayed.
3) Lethality may be modified by adequate supportive care and treatment. Of 17 pediatric cases reported prior to the use of deferoxamine, 8 (47%) resulted in death (Spencer, 1951; Forbes, 1947; Thomson, 1947; Thomson, 1950; Roxburgh, 1949).
4) For ferrous iron, the estimated lethal dose is 0.3 grams/kg body weight (Baselt, 2000).
5) Acute iron intoxication occurs more often in children than in adults, and is believed to be responsible for several hundred pediatric deaths annually (Baselt, 2000).
6) Fatal poisoning is accompanied with the following autopsy findings: hemorrhage and necrosis of gastrointestinal mucosa, degenerative changes in liver, and hemorrhagic bronchopneumonia (Baselt, 2000).
7) FATAL HEPATIC INJURY - The lowest serum iron level that was associated with hepatic injury was 1700 mcg/dL (304 mcmol/L) in a 17-year-old pregnant female who died of iron overdose-induced hepatic failure (Tenenbein, 2001).

B)

1) PEDIATRIC

a) In a series of 12 children who all received gastric lavage and deferoxamine, all survived (Whitten et al, 1965).
b) In a review of cases of children who developed severe iron intoxication, defined as coma or shock, definitive therapy (chelators, exchange transfusion) resulted in survival in 12 of 14 (86%), supportive care resulted in survival in 14 of 26 (54%), and no therapy resulted in survival in 0 of 10 (Whitten et al, 1965).
c) In another series of 28 children with shock or coma due to iron poisoning, 25 (89%) survived after deferoxamine therapy (Westlin, 1966).
d) TABLE of fatal PEDIATRIC iron ingestions

AGE (mo)	AMOUNT FERROUS SULFATE	AMOUNT ELEMENTAL IRON	TREATMENT	REF.
19	3 g (exsiccated)	900 mg	None	Spencer 1951
18	8.8 g (exsiccated)	2640 mg	Lavage	Spencer 1951
14	8 g (exsiccated)	2400 mg	None	Spencer 1951
16	5.2 g (exsiccated)	1560 mg	None	Thomson 1947
12	6 g to 7 g (exsiccated)	1800 mg to 1200 mg	Supportive	Forbes 1947
17	6 g	1200 mg	Methylene blue	Smith et al 1950
21	8.2 g (exsiccated)	2460 mg	Lavage	Smith 1952
26	9 g to 12 g	1800 mg to 2400 mg	Lavage	Duffy Diehl 1952
39	10 g (exsiccated)	3000 mg	None	Forbes 1947
20	10.2 g to 14.2 g	2040 mg to 2840 mg	Supportive	Clark et al 1954
12	12 g	2400 mg	Lavage	Haggerty 1960
16	22.5 g	4500 mg	Lavage	Charney 1961
18	16 g to 19.5 g	3200 mg to 3900 mg	EDTA Lavage deferoxamine	Gleason et al 1979

2) ADULT

a) TABLE of fatal ADULT iron ingestions

AGE (yr)	AMOUNT ELEMENTAL IRON	AMOUNT ELEMENTAL IRON/kg	TREATMENT	REF.
23	10 g	166 mg/kg	Supportive	Cernelc et al, 1968
*30	5 g	70 mg/kg	Deferox. (delayed 26 h)	Olenmark et al, 1987
UNK	2 g	UNK	Deferox. (delayed 27 h)	Lavender & Bell, 1970
UNK	10 g	UNK	Deferox. (delayed 72 h)	Henriksson et al, 1979
*UNK	5.4 g	UNK	Supportive	Strom et al, 1976
UNK	23 g	UNK	Supportive	Foucar et al, 1948
16	>/= 3 g	UNK	Supportive	Tenenbein et al, 1988
28	6.6 g	UNK	Deferox. (delayed 100 h)	Tenenbein et al, 1988
25	11.5 g**	230 mg/kg	Supportive	Wu et al, 1998
* = pregnant
** = ingestion of ferric chloride which was equivalent to 11.52 g or 230 mg/kg of elemental iron - deferoxamine not given secondary to rapid deterioration and late diagnosis
Deferox. = Deferoxamine

Maximum Tolerated Exposure

A)

B)

C)

D)

E)

F)

1) HAND WARMERS: One patient developed a "warm sensation" in her mouth and epigastrium after ingesting a piece of a hand warmer (Hot Hands 2) containing 5 to 8 grams of elemental iron. Laboratory results revealed a serum iron concentration of 235 mcg/dL obtained 6 hours postingestion. Some heat warmers may contain up to 60 g of iron powder (Weiland & Sherrow, 2015).
2) HIGH-DOSE DEFEROXAMINE: A 22-year-old woman with an extremely high serum iron concentration (4573 mcg/dL) after ingesting 180 tablets of 300 mg ferrous sulfate (216 mg/kg elemental iron), received high-dose IV deferoxamine (15 mg/kg/hr started 8 hours after ingestion, increased to 30 mg/kg/hr 2 hours later, and then decreased to 15 mg/kg/hr 4 hours later). Despite severe gastrointestinal complications and metabolic acidosis, she rapidly recovered following supportive care and did not developed any adverse effects from high-dose deferoxamine (Noble et al, 2015).
3) An 18-year-old woman presented with persistent vomiting, abdominal pain, lethargy, altered mental status, tachycardia (124 beats/min), and severe anion gap metabolic acidosis (pH 7.16, PaO2 122 mmHg, PCO2 20 mmHg, bicarbonate 6.9 mmol/L, base excess -21.5 mmol/L) about 8 hours after ingesting 50 ferrous sulfate tablets (100 mg of elemental iron per 335 mg tablet; 100 mg/kg of elemental iron). Following supportive care, including gastric lavage, whole bowel irrigation, continuous renal replacement therapies, continuous venovenous hemodiafiltration, and deferoxamine therapy, her condition gradually improved. Her serum iron concentration decreased from 2150 to 160 mcg/dL (reference range: 40 to 150 mcg/dL) 24 hours after ingestion (Gumber et al, 2013).
4) PEDIATRIC: An 18-month-old boy (weight 11 kg) presented with diarrhea and vomiting after ingesting about 1625 mg (147 mg/kg) of ferrous sulfate. He later became drowsy, requiring intubation and ventilation. X-ray of the abdomen revealed 13 tablet fragments. Despite standard therapy (gastric lavage, whole bowel irrigation, and intravenous deferoxamine 15 mg/kg/hr, total at least 360 mg/kg in 24 hours), his serum iron concentration increased to 700 mcmol/L (3906 mcg/dL) 6 hours after ingestion. He developed elevated ALT (359 Units/L) and coagulopathy with kaolin partial thromboplastin time at 74.5 s and prothrombin time at 16.5 s, requiring vitamin K, fresh frozen plasma, and cryoprecipitate. Approximately 14 hours postingestion, he underwent continuous veno-venous hemofiltration (CVVH) for 17 hours and his serum iron concentration quickly decreased to 24.5 mcmol/L (137 mcg/dL). Despite signs of organ damage, he gradually recovered and was discharged on day 5 (Milne & Petros, 2010).
5) PEDIATRIC - An 18-month-old girl (12 kg) presented to the emergency department after the ingestion of 5300 mg of iron (442 mg/kg of elemental iron; serum iron concentration of 447 mcg/dL on admission). Despite standard therapy (gastric lavage, whole bowel irrigation, and intravenous deferoxamine) for 2 hours, her serum iron increased to 1362 mcg/dL (244 mcmol/L). Exchange transfusion 9 hours post-ingestion reduced serum iron to 134 mcg/dL (24 mcmol/L). Her serum iron level decreased further to 40 mcg/dL (7 mcmol/L) after plasmapheresis for 5 hours. She was extubated 18 hours after the exchange transfusion (Carlsson et al, 2008).
6) PEDIATRIC - A 7-week-old girl was brought to the hospital 4 hours after the maternal grandmother accidently gave the infant approximately 1.5 ounces (400 mg/kg of elemental iron) of ferrous sulfate suspension from a baby bottle thought to contain juice. The infant was lethargic and shortly after arrival developed metabolic acidosis (pH 7.22; PCO2 58 mm Hg) and shock. Initial serum iron level was 671 mcg/dL, and the level decreased to 194 mcg/dL and 46 mcg/dL following 6 and 20 hours of deferoxamine chelation therapy, respectively. Treatment was complicated by the immaturity of the infant, but a full recovery without sequelae was noted at a follow-up several months after the incident (Valentine et al, 2009).
7) ADULT - Iron ingestions of 20 mg/kg by 6 fasted adults resulted in nausea, malaise, and diarrhea in all subjects, with 4 requiring intravenous fluids (Burkhart et al, 1991).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) PEDIATRIC

1) A serum iron concentration of 447 mcg/dL was reported in an 18-month-old girl (12 kg) after the ingestion of 5300 mg of iron (442 mg of elemental iron/kg). Despite standard therapy (gastric lavage, whole bowel irrigation and intravenous deferoxamine) for 2 hours, her serum iron increased to 1362 mcg/dL (244 mcmole/L). Exchange transfusion 9 hours postingestion reduced serum iron to 134 mcg/dL (24 mcmol/L). Her serum iron level decreased further to 40 mcg/dL (7 mcmol/L) after plasmapheresis for 5 hours. She was extubated 18 hours after the exchange transfusion (Carlsson et al, 2008).
2) In one series of 59 iron-poisoned children 15/20 with SI > 500 micrograms/deciliter were symptomatic and were considered to be moderately or severely poisoned (James, 1970). In addition to similar findings by James (1970), Chyka & Butler (1993) found a significant correlation between serum iron levels above 500 micrograms/deciliter and coma (Chyka & Butler, 1993).
3) Nine of 13 with SI < 300 micrograms/deciliter were mildly poisoned or asymptomatic.
4) Of 22 patients with initial levels between 300 and 500 micrograms/deciliter, 14 were moderately or severely poisoned and 8 were mildly poisoned or asymptomatic (James, 1970).
5) HIGHEST REPORTED SERUM IRON LEVELS

a) SURVIVAL - 16,706 micrograms/deciliter in a 22-month-old male who survived with aggressive treatment (Benson & Cheney, 1992).
b) FATALITY - Serum iron level of 18,570 micrograms/deciliter was reported in a 17-month-old who died despite early diagnosis (presented one hour postingestion), GI decontamination with whole bowel irrigation, IV deferoxamine, endoscopy, and gastrotomy (Perrone et al, 2000).

b) ADULT

1) FATAL ACUTE OVERDOSE: Initial serum iron level was 2385 micrograms/deciliter in an adult who was treated with deferoxamine and later died (Michelson et al, 1992).
2) HIGH-DOSE DEFEROXAMINE: A 22-year-old woman with an extremely high serum iron concentration (4573 mcg/dL) after ingesting 180 tablets of 300 mg ferrous sulfate (216 mg/kg elemental iron), received high-dose IV deferoxamine (15 mg/kg/hr started 8 hours after ingestion, increased to 30 mg/kg/hr 2 hours later, and then decreased to 15 mg/kg/hr 4 hours later). Despite severe gastrointestinal complications and metabolic acidosis, she rapidly recovered following supportive care and did not developed any adverse effects from high-dose deferoxamine (Noble et al, 2015).

Workplace Standards

A)

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Iron salts, soluble, as Fe

a) TLV:

1) TLV-TWA: 1 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Not Listed
3) Definitions: Not Listed

c) TLV Basis - Critical Effect(s): URT and skin irr
d) Molecular Weight: Varies

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS7439-89-6 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Iron salts (soluble, as Fe)
2) REL:

a) TWA: 1 mg/m(3)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s):

3) IDLH: Not Listed

C) Carcinogenicity Ratings for CAS7439-89-6 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Iron salts, soluble, as Fe
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Iron salts (soluble, as Fe)
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D) OSHA PEL Values for CAS7439-89-6 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Not Listed

Toxicity Information

7.7.1)

A) References: Clayton & Clayton, 1994 Lewis, 1996 OHM/TADS, 1999 RTECS, 1999

1) LD50- (ORAL)RAT:

a) 30 g/kg

2) TCLo- (INHALATION)RAT:

a) 250 mg/m(3) for 6H/4W-I -- caused chronic pulmonary edema and other changes

Pharmacology Toxicology

Pharmacologic Mechanism

A)

1) In a healthy man, iron loss is replaced absorption of approximately 1 milligram of iron daily, in women average loss is approximately 2 milligrams daily.

Toxicologic Mechanism

A)

B)

Physicochemical

Physical Characteristics

A)

B)

1) Iron (chemical symbol Fe, from the Latin word ferrum) has the atomic number 26 and belongs to the Group VIII transition elements of the periodic table (Clayton & Clayton, 1994).
2) Iron can be rolled, hammered, and bent, particularly when red hot (Budavari, 1996).
3) Iron's magnetism is held only after hardening (as alloy steel, such as Alnico) (Budavari, 1996).
4) Iron is supplied as ingots, powder, wire, sheets, and other forms (Budavari, 1996).
5) Iron is stable in dry air and readily oxidizes in moist air, forming "rust" (Budavari, 1996).
6) Commercial forms of iron usually contain carbon (C), phosphorus (P), silicon (Si), sulfur (S) and manganese (Mn) (Budavari, 1996).
7) Iron is the only metal that can be tempered (Lewis, 1997).

C)

D)

Ph

A)

B)

Molecular Weight

A)

B)

C)

D)

Animal Toxicology

Clinical Effects

11.1.5)

A) FERROUS FUMARATE/LACTOBACILLUS PREPARATION - Was responsible for a rash of deaths in neonatal foals. Signs included: severe depression, icterus, and increased SGPT, PCV, alkaline phosphatase, prothrombin time, total bilirubin, and plasma NH3. Death occurred at 2 to 5 days of age due to acute hepatic failure (Mullaney & Brown, 1988).

11.1.10)

A) Baby pigs are most susceptible and may be poisoned by iron dextran injections. Two clinical syndromes: peracute, an anaphylactic shock reaction characterized by vascular collapse and rapid death; subacute, characterized by bloody diarrhea and vomiting and drowsiness, followed by some improvement, then steady deterioration, cardiovascular collapse, and death.

11.1.13)

A) OTHER

1) GENERAL DESCRIPTION, SUBACUTE - Vomiting and diarrhea (often bloody) develop 0 to 6 hours postingestion. Apparent recovery occurs 6 to 24 hours postingestion. Acidosis, GI hemorrhage, CNS depression, liver failure, and shock with secondary acute renal failure then develop prior to death.

Treatment

11.2.1)

A) GENERAL TREATMENT

1) SUMMARY

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Remove the patient and other animals from the source of contamination or remove dietary sources.

2) Treatment should always be done on the advice and with the consultation of a veterinarian.
3) Additional information regarding treatment of poisoned animals may be obtained from a Veterinary Toxicologist or the National Animal Poison Control Center.
4) ASPCA ANIMAL POISON CONTROL CENTER

a) ASPCA Animal Poison Control Center, 1717 S Philo Road, Suite 36 Urbana, IL 61802
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) Contact information: (888) 426-4435 (hotline) or www.aspca.org (A fee may apply. Please inquire with the poison center). The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

a) EMESIS/GASTRIC LAVAGE -

1) CAUTION: Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
2) HORSES OR CATTLE: DO NOT attempt to induce emesis in ruminants (cattle) or equids (horses).
3) DOGS AND CATS

a) IPECAC: If within 2 hours of exposure: induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
b) APOMORPHINE: Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.

1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective.

4) LAVAGE: In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.

a) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.

b) ORAL CHELATING AGENTS -

1) These agents are used after gastric decontamination and do not replace parenteral chelation in serious cases.
2) Magnesium oxide (Milk of Magnesia) complexes with iron to form FeOH which precipitates and is not absorbed (Beasley et al, 1990). However, in some cases the formation of insoluble iron may be at a slower rate, and less than 20% of the iron is transformed to the insoluble form. Rate of precipitation may be slow and less than 20% of the iron may be precipitated.

11.2.5)

A) GENERAL TREATMENT

1) ANAPHYLAXIS -

a) AIRWAY: Maintain a patent airway via endotracheal tube or tracheostomy.
b) FLUIDS:

1) HORSES: Administer electrolyte and fluid therapy as needed. Maintenance dose of intravenous isotonic fluids: 10 to 20 milliliters/ kilogram per day. High dose for shock: 20 to 45 milliliters/kilogram/hour.

a) Monitor for packed cell volume, adequate urine output and pulmonary edema. Goal is to maintain a urinary flow of 0.1 milliliters/kilogram/minute (2.4 liters/hour for an 880 pound horse).

2) CATTLE: Administer electrolyte and fluid therapy, orally or parenterally as needed. Maintenance dose of intravenous isotonic fluids for calves and debilitated adult cattle: 140 milliliters/kilogram/day. Dose for rehydration: 50 to 100 milliliters/kilogram given over 4 to 6 hours.
3) SMALL ANIMALS: If necessary, begin fluid therapy at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour). Monitor for urine production and pulmonary edema.

c) EPINEPHRINE:

1) HORSES: 3 to 5 milliliters/450 kilograms of 1:1000 epinephrine intramuscularly or subcutaneously.
2) CATTLE & SWINE: 0.02 to 0.03 milligrams/kilogram of 1:1000 epinephrine subcutaneously, intramuscularly, or intravenously.
3) SMALL ANIMALS: For severe reactions.

a) DOGS: 0.5 to 1 milliliter of 1:10,000 (DILUTE) solution intravenously or subcutaneously
b) CATS: 0.5 milliliters of 1:10,000 (DILUTE) solution intravenously or intramuscularly. Be sure to dilute epinephrine from the bottle (1:1000) one part to 9 parts saline to obtain the correct concentration (1:10,000). If indicated, dose may be repeated in 20 minutes.

d) ANTIHISTAMINES/STEROIDS (DOGS & CATS):

1) Doxylamine succinate (1 to 2.2 milligram/kilogram subcutaneously or intramuscularly every 8 to 12 hours)
2) or dexamethasone sodium phosphate (1 to 5 milligram/kilogram intravenously every 12 to 24 hours)
3) or prednisolone (1 to 5 milligram/kilogram intravenously every 1 to 6 hours).

2) SUPPORTIVE TREATMENT -

a) Begin electrolyte and fluid therapy with isotonic solutions as needed at maintenance doses (66 milliliters solution/kilogram body weight/day intravenously) or, in hypotensive patients, at high doses (up to shock dose 60 milliliters/kilogram/hour). Monitor for urine production and pulmonary edema.
b) BICARBONATE: Add sodium bicarbonate to the intravenous fluids if metabolic acidosis is suspected. (If using lactated ringers solution and precipitate forms upon addition of bicarbonate, discard and substitute a different solution).

1) Formula for bicarbonate addition when blood gases are available: milliequivalents bicarbonate added = base deficit x 0.5 x body weight in kilograms. Give one half of the determined dose slowly over 3 to 4 hours intravenously; titrate as needed.
2) Continue to dose based on blood gas determinations. When blood gases are not available and patient is symptomatic, administer 1 to 4 milliequivalents/kilogram intravenously slowly over 4 to 8 hours.

3) GASTRIC IRRITATION -

a) Observe patients with ingestion carefully for esophageal or laryngeal burns; if burns are present, consider esophagoscopy to determine their extent.
b) SUCRALFATE: For relief of gastric irritation or ulceration, administer sucralfate as follows: DOGS: (body weight less than 20 kilograms) 500 milligrams three to four times daily; (weight greater than 20 kilograms) one gram three to four times daily.

1) Give sucralfate one hour before feeding and wait two hours prior to cimetidine dosing.

c) CIMETIDINE:

1) DOGS: 5 to 10 milligrams/kilogram per os, intravenously, or intramuscularly every 6 to 8 hours
2) CATS: 2.5 to 5 milligrams/kilogram per os, intravenously, or intramuscularly every 8 to 12 hours

4) DEFEROXAMINE MESYLATE - DESFERAL

a) Deferoxamine (Desferal (R)) is a chelation agent available at human hospitals to enhance the excretion of iron. Dose: 40 milligrams/kilogram intramuscularly every 4 to 8 hours. Desferal may also be given intravenously at a rate of less than 15 milligram/kilogram/ hour.
b) Manufacturer recommends the use of the intravenous dose be reserved for patients in a state of cardiovascular shock, however it is frequently used in other settings. If given too rapidly, Desferal will cause hypotension and shock.
c) The urine usually turns a reddish-brown color; therapy is continued until the urine no longer changes color or until clinical condition has improved.
d) It should be used in moderately to severely toxic patients, and in those patients whose serum iron concentration equals or exceeds 300 micrograms/deciliter.
e) ASCORBIC ACID - When given in large oral doses along with deferoxamine may double the iron excretion (Beasley et al, 1990).

5) MONITORING -

a) Admit all symptomatic patients and begin treatment.
b) Doses less than 20 milligrams/kilogram:

1) Observe asymptomatic patients for 8 hours in the primary care clinic.

c) Doses of 20 to 60 milligrams/kilogram:

1) Observe asymptomatic patients for 24 hours in the primary care clinic.
2) Unless life threatening signs develop, these patients may be kept in the primary care clinic (24 hour monitoring is not necessary).

d) Doses greater than 60 milligrams/kilogram:

1) Symptomatic patients must be monitored continuously. Refer to an emergency hospital or critical care clinic for 24 hour monitoring.

6) FOLLOW-UP -

a) Instruct the owner to return for a follow up appointment at which physical examination and appropriate laboratory tests will be repeated.

Range Of Toxicity

11.3.2)

A) GENERAL

1) LETHAL - Oral doses greater than 200 to 300 milligrams/kilogram (Beasley et al, 1990)
2) POTENTIALLY SERIOUS - Oral dose of elemental iron greater than 60 milligrams/kilogram (Beasley et al, 1990)
3) POTENTIALLY TOXIC - Oral dose of elemental iron between 20 and 40 milligrams/kilogram (Beasley et al, 1990)

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) SUMMARY

a) Begin treatment immediately.
b) Keep animal warm and do not handle unnecessarily.
c) Remove the patient and other animals from the source of contamination or remove dietary sources.

2) Treatment should always be done on the advice and with the consultation of a veterinarian.
3) Additional information regarding treatment of poisoned animals may be obtained from a Veterinary Toxicologist or the National Animal Poison Control Center.
4) ASPCA ANIMAL POISON CONTROL CENTER

a) ASPCA Animal Poison Control Center, 1717 S Philo Road, Suite 36 Urbana, IL 61802
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) Contact information: (888) 426-4435 (hotline) or www.aspca.org (A fee may apply. Please inquire with the poison center). The agency will make follow-up calls as needed in critical cases at no extra charge.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) GENERAL TREATMENT

a) EMESIS/GASTRIC LAVAGE -

1) CAUTION: Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
2) HORSES OR CATTLE: DO NOT attempt to induce emesis in ruminants (cattle) or equids (horses).
3) DOGS AND CATS

a) IPECAC: If within 2 hours of exposure: induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.
b) APOMORPHINE: Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.

1) Dogs may also be given apomorphine intravenously at 40 micrograms/kilogram, although this route may not be as effective.

4) LAVAGE: In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.

a) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.

b) ORAL CHELATING AGENTS -

1) These agents are used after gastric decontamination and do not replace parenteral chelation in serious cases.
2) Magnesium oxide (Milk of Magnesia) complexes with iron to form FeOH which precipitates and is not absorbed (Beasley et al, 1990). However, in some cases the formation of insoluble iron may be at a slower rate, and less than 20% of the iron is transformed to the insoluble form. Rate of precipitation may be slow and less than 20% of the iron may be precipitated.

11.4.3)

11.4.3.5) SUPPORTIVE CARE

A) GENERAL

1) Ongoing treatment is symptomatic and supportive.

11.4.3.6) OTHER

A) OTHER

1) GENERAL

a) LABORATORY -

1) Iron tablets may be visualized in the stomach with an abdominal radiograph. Dissolved tablets may not show on radiograph.
2) Serum iron measurements and total iron binding capacity, while infrequently used by veterinarians, would provide diagnostic documentation.
3) In symptomatic patients, monitor periodic CBC (including PCV and hematocrit), hepatic enzymes and function tests, and BUN and creatinine.

Sources

A)

1) Injectable iron dextran (given to baby pigs) is the most common source of poisoning. Another common source is human preparations of iron tablets or multivitamins with iron, which may be ingested in large quantities by dogs.

References

General Bibliography

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FeedBack

IRON

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Endocrine

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Eye Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Sources

General Bibliography